INCOMPATIBILITY

INCOMPATIBILITIES

It is the result of prescribing or mixing two or more substances which

are antagonist( against) in nature and an undesirable(unwanted)
product is formed which may affect the safety, efficacy or
appearance of the preparation.
Incompatibilities are usually unintentional.
 It may occur in vitro between drugs & other components during
preparation, storage or administration.
Incompatibility may be :
1.Pharmaceutical /Physical Incompatibility
2.Therapeutic Incompatibility
3.Chemical Incompatibility
 Physical Incompatibility

 A visible physical change takes place

 An unacceptable, non-uniform, unpalatable product is

formed.

 Difficult to measure an accurate dose.

 Result of insolubility and immiscibility, precipitation,

liquefaction, Adsorption and complexation of solid
materials.

 Can be corrected by applying pharmaceutical skill

 Physical Incompatibility

Examples of physical incompatibility:

Immiscibility

Insolubility

Precipitation

liquefaction
CORRECTION(PHYSICAL
INCOMPATIBILITIES )

By one or more methods:

1. Order of mixing
2.alteration of solvents
3.change in the form of ingredients
4. alteration of volume
5.Emulsification and addition of suspending
agent,
6.addition, substitution or omission of
therapeutically inactive substances.
INCOMPATIBILITY

TYPE OF
INCOMPATIBILITY

THERAPEUT
PHYSICAL
IC
CHEMICA
L
EXAMPLES
TYPES EXAMPLES

1.IMMISCIBILIT 1. TOLERATE 1.PRECIPITATION

Y D 2.COLOUR CHANGE
2. 2.ADJUSTED
2.INSOLUBILITY 3.EFFERVESCENCE
3.PRECIPITATIO 4.DECOMPOSITION
N
 1. Immiscibility

 It is the result of the mixture of two or more immiscible liquid or an immiscible

solid with a liquid.

 Acceptable liquid product can be obtained by emulsification or solubilization.

Rx

Olive oil 30ml

Water up to 120ml

make an emulsion

use a suitable emulsifying agent

 2. Insolubility

 Liquid preparation with Indiffusible solids (e.g. Sulphamethoxasole, phenacetin,

Zinc oxide, calamine etc.) a suspending agent is required to uniform distribution of
the solids in the liquid phase for sufficiently long time so as to facilitate accurate
measurement of dose.
1) Rx

Sulphamethoxazole 4.0g
Trimethoprim 0.8g
Na- CMC 0.5g
Purified water qs to 100ml

Prepare a solution.

Sulphamethoxazole &Trimethoprim are indiffusible in water.

To make them diffusible a suspending agent is used.
2. Insolubility

2) Insoluble Powders such as Sulphur, certain corticosteroids and Antibiotic

is not get wetted with water & non – distributed in vehicle & hence wetting
agents such as Saponins & Polysorbates are added for uniform distribution of
it in vehicle.

Insoluble non-wetted drug Powders + Water + wetting Agent

(polysorbates/saponins)
3. Precipitation

 A solubilised substance may precipitate from it solution if a

non solvent for the substance is added to the solution.

1. Alcoholic solution of Resins + water = precipitated Resins

2. Aqueous dispersion of Hydrophillic colloids (polysaccharide mucilage

+ high conc. of Alcohol or salts = Precipitated colloids.

But significant amount are tolerated if well diluted and added in small
amount with vigorous stirring
 4. Liquefaction

Certain low melting point solids sometimes liquefy when mixed together due to the
formation of eutectic mixture or liberation of water .

e.g, if any 2 of the following medicaments are combined together, they form a eutectic
mixture:

Menthol, Thymol, Camphor, Phenol, Salol, Naphthol and chloral hydrate.

Sodium salicylate Phenazone.

Correction:-

1. The eutectic forming ingredient may either be dispensed separately

2. These may be mixed separately with enough quantity of adsorbent powder like
magnesium carbonate or Kaolin to form free flowing product.

3. Alternately, if liquefaction has already occurred, the liquid may be adsorbed on a

surface of sufficient quantity of powder , filled into capsule and dispensed
Example:

Rx
Menthol 2.0g
Camphor 2.0g
Ammonium carbonate 20.0g

Make a powder.

 In this case, if the ingredients are mixed together, they shall liquefy due to
formation of a eutectic mixture.
 Hence, to dispense them in the form of a powder, it is necessary to mix
them separately with sufficient quantity of a suitable adsorbent like
magnesium carbonate.
 The three mixture then mix together to obtain a powder.
CHEMICAL INCOMPATIBILITIES

 Chemical Incompatibilities is usually a result of chemical interaction

taking place among the ingredients of a prescription.

 Such interactions may take place immediately upon compounding when

these are termed as immediate incompatibilities and are evident as
effervescence, precipitation or colour change.

 More often the interaction are not evident immediately on compounding

but take place over a period of time. Such interaction are termed
delayed incompatibilities.
a. Tolerated-:

The reaction is minimized by applying some suitable order of mixing or mixing the

solution in dilute form but no alteration is made in the active ingredients of the

preparation.

b. Adjusted-:

The reaction is prevented by addition or substitution of one of the reacting

substances with another of equal therapeutic value but does not affect the medicinal

of the preparation (substitution of caffeine citrate with caffeine in sodium salicylate

and caffeine citrate mixture)

a) Intentional compatibility-:

When the prescriber knowingly prescribes the incompatible drugs.

b. Unintentional compatibility- -:

When the prescriber prescribes the drugs without knowing that there is

incompatibility between the prescribed drugs.

Precipitate yielding combination

Generally reaction between strong solutions proceed at a faster rate and the
precipitates formed are thick and do not diffuse readily.

Reaction between the dilute solutions proceed at a slow rate and the precipitates
formed are light and diffuse readily in the solution.

Hence the reacting substances should be diluted as much as possible before

mixing.
The preparation should contain a thickening agent if the precipitate is non-
diffusible.
Precipitate yielding combination

DIFFUSIBLE SOLIDS
Precipitate yielding combination

INDIFFUSIBLE SOLIDS
 Method A

This is suitable for diffusible precipitates

1.Divide all or most of the vehicle into two portions
2.Dissolve the reactants in separate portions
3.Mix the two portions by slowly adding one to the other with
stirring rapidly.
(Sometimes a small volume must be reserved for dissolving other
ingredients, rinsing measures, and adjusting to volume.)
Method A
Method B

It is used for bulky indiffusible precipitates.

1.Divide the vehicle into two equal portions as in A

2.Dissolve one reacting substance in one portion

3. Place the other portion in a mortar and Incorporate a suitable amount of

Tragacanth powder (2gm/100ml of the finished product) with constant
trituration until a smooth mucilage is produced, then add and dissolve the other
reacting substances.

4.Mix the two portions by slowly adding one portion to the other with rapid
stirring.
Method B
CHEMICAL INCOMPATIBILITY
Chemical Incompatibility

A. Alkaloid incompatibility:-
1. Alkaloidal salts with alkaloid substances
2. Alkaloidal salts with soluble iodides
3. Alkaloidal salts with tannins
4. Alkaloid salts with salicylates
5. Alkaloid with soluble iodides and bromides.

B. Soluble salicylates incompatibility:-

1.Soluble salicylates with ferric salts
2.Soluble salicylates with alkali bicarbonates
3.Soluble salicylates and benzoates with acids.

C. Soluble iodides incompatibility:-

1.Oxidation of iodides with potassium chlorate
2.Oxidation of iodides with quinine sulphate.
chemical Incompatibility

D. Chemical incompatibility causing evolution of

carbon dioxide gas:-
1.Sodium bicarbonate with soluble calcium or magnesium

salts
2.Bismuthsubnitrate and sodium bicarbonate
3.Borax with sodium bicarbonate and glycerin.

E. Miscellaneous incompatibilities:-
1.Soluble barbiturates with ammonium bromide
2.Potassium chlorate with oxdisible substances
3. Incompatibility of emulsifying agent
4. Color stability of dyes
5. Incompatibilities of liquorices liquid extract
Alkaloidal Incompatibility
◦ Alkaloid + salt= alkaloidal salt
◦ Alkaloidal salt+alkaline substances= diffusible ppt(alkaloid)
◦ Alkaloid salt+ salicylate=diffusible ppt
◦ Alkaloid salt+ iodide=diffusible ppt(in the form of hydroiodide)
◦ Alkaloid salt+ iodide or bromide =diffusible ppt
◦ Alkaloid salt+ tannins=diffusible ppt(tannates)
Soluble salicylates incompatibility

1.Soluble salicylates + ferric salts indiffusible ppt(method B)

2.Soluble salicylates + alkali bicarbonatesprecipitate(neutralize)

3.Soluble salicylates and benzoates with acids.indiffusible ppt(method

B)
Alkaloidal Incompatibility

1. Alkaloidal salt with alkaline substances …

Alkaloids are weak bases.They are almost insoluble in water

but alkoidal salts are soluble in water but alkaloidal salts are
soluble in water
If these salts are dispensed with alkaline preparations, the free
alkaloid may be precipitated.
However they are not always precipitated, because all
alkaloids are slightly soluble in water and other added
substances.
Alkaloidal Incompatibility

1. Alkaloidal salt with alkaline substances …

Example:

Rx
Strychnine hydrochloride solution 6ml
Aromatic spirit of ammonia 4ml
Purified water upto 120ml
make a mixture.
Alkaloidal Incompatibility
1. Alkaloidal salt with alkaline substances …

 Strychnine hydrochloride is an alkaloidal salt whereas aromatic spirit of ammonia is an

alkaline substance.

 When they react together,they gets precipitated because the quantity of strychnine

hydrochloride prescribed in the prescription is much more than its solubility in water.

 The aromatic spirit of ammonia contains negligible amount of alcohol which cannot

dissolve the strychnine.

 Hence it gets precipitated as diffusible precipitate.

 Hence follow method A for precipitate yielding combination.

Alkaloidal Incompatibility
Alkaloidal Incompatibility
1. Alkaloidal salt with alkaline substances …
Example:
Rx
Ammonium bicarbonate 1.5 gm
Sodium bicarbonate 4.5 gm
Tincture ipecac 8.33 ml
Chloroform water 100 ml
make a mixture.
Tincture ipecac contains an alkaloid emetine.the insolubility of emetine is 1;1000.
1ml of tincture ipecac contains 0.15 gm of emetine.
Ammonium bicarbonate and sodium bicarbonate are alkaline substances.
The prescribed amount of tincture ipecac will not give precipitation in the mixture.
Therefore a simple mixture is formed.
Alkaloidal Incompatibility
2. Alkaloidal salt with soluble iodides …

 In cough mixture, potassium iodide is generally prescribed as an expectorant along

with tincture ipecacuanha( containing emetine).

 The quantity of emetine present is usually low that it cannot react with potassium

iodide to get precipitated as hydro iodide.

 Similarly when strychnine is prescribed along with soluble iodides it forms a very

insoluble hydroiodide,the precipitates of which are diffusible.

 Hence follow method A for the precipitate yielding interaction.

Alkaloidal Incompatibility
3. Alkaloidal salt with tannins …

The alkaloidal salts when combined with a drug containing

tannins,the alkaloids form tannates which are separated as

diffusible precipitates.

So follow method A for precipitate yielding interaction.

The tannates of most alkaloids are insoluble in water; hence

strong tea or tannic acid solution is commonly used in alkaloidal

poisoning.
Alkaloidal Incompatibility
4. Alkaloidal salt with salicylates …
When quinine compounds are combined with salicylates,
they form indiffusible precipitates of quinine salicylates. So
follow method B for precipitate yielding interaction.
Example;
Rx
Quinine hydrochloride 0.12 gm
Sodium salicylate 4 gm
water 100 ml
make a mixture.
Method B should be followed .
Alkaloidal Incompatibility
4. Alkaloidal salt with salicylates …
Alkaloidal Incompatibility
4. Alkaloidal salt with salicylates …
Rx
Caffeine citrate 1 gm
Sodium salicylate 3 gm
water 90 ml
make a mixture
Caffeine citrate is a mixture of equal weights of caffeine &
citric acid.
The citric acid present in caffeine citrate reacts with sodium
salicylate to liberate salicylic acid which get precipitated.
If caffeine is used instead to form a clear mixture.
Alkaloidal Incompatibility
5. Alkaloidal salt with soluble iodides and
bromides…
Rx
Potassium iodide 1.5 gm
Tincture of stramonium 8.5 ml
Chloroform water 100 ml
Tincture stramonium contains solanaceous alkaloid,which
form diffusible precipitates of hydroiodides with potassium
iodide.so follow method A in dispensing this prescription.
Alkaloidal Incompatibility
5. Alkaloidal salt with soluble iodides and
bromides…
Rx
Potassium iodide 1.5 gm
Tincture of stramonium 8.5 ml
Chloroform water 100 ml
Tincture stramonium contains solanaceous alkaloid,which
form diffusible precipitates of hydroiodides with potassium
iodide.so follow method A in dispensing this prescription.
Soluble salicylate Incompatibility
1. Soluble salicylates with ferric salts
Rx
Ferric chloride solution 2ml
Sodium salicylate 3gm
water 90 ml
Ferric chloride + sodium salicylate  ferric salicylate
( in diffusible ppt)
Follow method B
Soluble salicylate Incompatibility
1. Soluble salicylates with ferric salts
Rx
Ferric chloride solution 2ml
Sodium salicylate 3gm
Sodium bicarbonate 8gm
water 90 ml
Dissolve sodium salicylate and sodium bicarbonate in
about 70ml of water.
Add the ferric chloride solution, effervescence is produced.
When effervescence is ceased filter through cotton wool
and make up the volume .
Soluble salicylate Incompatibility
Soluble salicylate Incompatibility
2. Soluble salicylates with alkali bicarbonates
Rx
Sodium salicylate 8gm
Sodium bicarbonate 8gm
Sodium metabisulphite 0.08gm
chloroform water 12 0 ml
Make a mixture
When sod.salicylate dispense with sodium bicarbonate, the mixture
absorbs oxygen from atmosphere and become reddish brown in colour.it
doesn’t affect the efficiency of product but may confused the patient.

So to avoid the color change, sodium metabisulphite is added.

Soluble salicylate Incompatibility
3. Soluble salicylates benzoates with acids
Rx
Sodium salicylate 3gm
Syrup of melon 15 ml

water 60 ml
Make a mixture
Syrup of lemon contains citric acid.

When it reacts with sodium salicylate,salicylic acid will be precipitated as

indiffusible solid

It can be avoided in 2 ways,

1.Method B 2. LEMON SYRUP substituted with TINCTURE LEMON

Soluble iodides Incompatibility
Iodides undergo oxidation forming “iodine” which is an
UNDESIRABLE product.
Hence the following steps should be taken to avoid this
chemical change.
i)Oxidation of iodides with ferric salts:
When ferric salts reacts with soluble iodide it gets converted
to ferrous salt. There is no satisfactory method to adjust this
incompatibility.
 Fe³⁺ + 2I Fe²⁺ +  I2

To prevent the incompatibility the prescriber may

substitute ferric salts with ammonium citrate &
iron.iron is converted into organic compound which
does not yield ferric ions.
Soluble Iodides Incompatibility
Eg.: Prepare and dispense 90ml of thefollowing mixture.
Rx
Ferric chloride solution 1.5ml
Potassium iodide 3gm
Potassium citrate 6gm

water 90 ml
Direction: one tablespoonful to be taken two times a day
Ferric chloride solution reacts with potassium iodide to liberate
free iodine
 2FeCl3 + 2KI   2FeCl2 + 2KCI +  I2
Soluble Iodides Incompatibility

To prevent the liberation of iodine in the mixture, the ferric

chloride is converted into organic compound before the
addition of potassium iodide.
METHOD: Dissolve potassium citrate in about three fourth
of water .add ferric chloride solution and then potassium
iodide. Add more water to adjust the volume. The color of the
mixture is green due to formation of new compound by the
reaction between ferric chloride and pot citrate
 
FeCl3 + C6H5K3O7   C6H5FeO7 + 3KCI
Pot.citrate ferric citrate
Soluble Iodides Incompatibility
ii) Oxidation of iodides with potassium chlorate
When soluble iodides reacts with potassium chlorate, it liberates
iodine.
KClO3 +  3FeI2  3FeOI +3I+KCL
To prevent this incompatibility, the two reacting
substances must be dispensed separately.
Rx
Potassium chlorate 4gm
Syrup of ferric iodide 6ml

water 180 ml
The freshly prepared mixture is clear but upon standing for
sometime,crystals of iodine get deposited.to prevent it dispense
separately and direct to patient.
Soluble Iodides Incompatibility
iii) Oxidation of iodides with quinine sulphate
Quinine sulphate is not freely soluble in water.it is made soluble in presence of dilute sulphuric acid. the
sulphuric acid liberates hydroiodic acid from the potassium iodide,7 then the hydroiodic acid is partly
oxidized by the sulphuric acid yielding iodine .The iodine , hydro iodic acid and quinine sulphate then
combine to form a compound called ‘herapathite’or ‘iodosulphide of quinine’.
The compound has a following formula

(C20H24N2O4) . H2SO4 .2HI .  2I2 . 6H2O

This incompatibility can be removed by following method:
1.Patient should be supplied with a mixture of 3 days only.
2.In case patient require a mixture more than 3 days both the solutions are prepared in half the volume of
water and supplied in separate bottle.

Rx
Potassium chlorate 4gm
Syrup of ferric iodide 6ml
water 180 ml
The freshly prepared mixture is clear but upon standing for sometime,crystals of iodine get deposited.to
prevent it dispense separately and direct to patient.
 Example :prepare and dispense 200ml of
following mixture.
Rx
Quinine sulphate 1.5g
Dilute sulphuric acid 4ml
Potassium iodide 8gm
Water 200ml
make a mixture.
◦Dilute the sulphuric acid with 100ml of water and dissolve the quinine
sulphate into it . the potassium iodide is added in remaining portion of
water and then mixed with first portion , the mixture formed is quite clear
at first but after about three days it may deposit bronze scales or olive
green scales which may due to herapath reaction.
Example :prepare and dispense 200ml of
following mixture.
Example :prepare and dispense 200ml of
following mixture.
◦ ANOTHER METHOD IF QUANTITY IS REQUIRED MORE
Chemical incompatibility causing
evolution of carbon dioxide gas

◦ When carbonates or bicarbonates are dispensed in the presence of acids or

acidic drugs in a mixture , they react together with the evolution of carbon
dioxide gas.
◦ If the reaction is not allowed to complete before transferring the mixture into a
dispensing bottle and cooked , there are chances of explosion of bottle.
◦ To prevent explosion, the reaction must be completed before dispensing the
mixture.
◦ To speed up the reaction , mix the ingredients in an open vessel and allow the
reaction to complete until effervescence ceases , hot water can also be used to
hasten the reaction.
Chemical incompatibility causing
evolution of carbon dioxide gas
1. sodium bicarbonate with soluble calcium or magnesium salts:
When sodium bicarbonate is combined with soluble calcium or magnesium salts
due to double decomposition reaction , there is formation of insoluble
carbonate and carbon dioxide.
MgSO4 + 2NaHCO₃ Mg (HCO₃) 2 + Na2SO4

4Mg (HCO₃) 2 3MgCO3 + Mg(OH)2 + 5CO2 + 3H2O

The reaction proceeds slowly at ordinary temperature.to accelerate the reaction
hot water should be used. the mixture should be dispensed only when
effervescence ceases.
The precipitates of carbonates formed are diffusible in nature so follow
METHOD A
Chemical incompatibility causing
evolution of carbon dioxide gas
2. Bismuth sub nitrate and sodium bicarbonate :
When bismuth sub nitrate is combined with sodium bicarbonate in the presence of
water there is formation of carbon dioxide due to following reaction.
2BiONO3 + 2NaHCO₃ (BiO)2 CO₃ + 2NaNO3 + 5CO2 + 3H2O

The reaction proceeds slowly at ordinary temperature.to accelerate the reaction hot
water should be used. the mixture should not be transferred to a bottle until the
effervescence ceases.
Chemical incompatibility causing
evolution of carbon dioxide gas
3. Borax with sodium bicarbonate and glycerin:
When borax is combined with water the sodium metaborate and boric acid is
formed.
Na₂B₄O7 + 3H2O Na ₂OB ₂O ₃ +  H3BO3
The boric acid so formed reacts with glycerin to form monobasic glyceryl boric
acid which liberate carbon dioxide from the bicarbonate. To hasten the reaction , it
should be mixed in open vessel using hot water as a vehicle.
C3H8O3 + 3H3BO3 (C3H5)2(H3BO3) 3 +   6H2O
glyceryl-boric acid
Mixture should not be transferred to bottle until effervescence ceases.
Miscellaneous Chemical incompatibility

1.Soluble barbiturates with ammonium bromide

Barbiturates + ammonium bromide barbitone (indiffusible ppt)
Follow METHOD B

EXAMPLE:
Rx
Phenobarbitone sodium 0.6g
Ammonium bromide 8g
Water upto 100ml
Make a mixture
Miscellaneous Chemical incompatibility
Miscellaneous Chemical incompatibility

2. Potassium chlorate with oxidisable substances

When potassium chlorate treated with oxidisable substances like
charcoal,sulphur,sugar organic compounds.

If during dispensing heating or trituration is done, there are chances of

explosion.

Mixing of pot. Chlorate with any substance is not advisable

But if essential, the ingredients should be powdered separately in a dry or

clean mortar and then mixed with clean powder spatula gently on a clean
ointment tile without friction.
Miscellaneous Chemical incompatibility

2. Potassium chlorate with oxidisable substances

Miscellaneous Chemical incompatibility

3. Incompatibility of emulsifying agents:

Emulsions prepared with alkali metal, ammonium and

triethanolamine soaps are incompatible with salts
producing polyvalent cations.

Due to double decomposition a polyvalent soap is formed

which inverts the emulsion.

Sometimes an emulsifying agent cause an inversion in

emulsion product.
Miscellaneous Chemical incompatibility

3. Incompatibility of emulsifying agents:

Miscellaneous Chemical incompatibility
4. Colour stability of dyes:
Miscellaneous Chemical incompatibility
5. Incompatibilities of liquor ice liquid extract:
THERAPEUTIC INCOMPATIBILITY
 It may be the result of prescribing certain drugs to the
patient with the intention to produce a specific degree of
action but the nature or the intensity of the action produced
is different from that intended by the prescriber.
CAUSES:
It may be due to the administration of :
 Overdose or improper dose of a single drug.
 Improper Dosage form.
 Contraindicated drug.
 Synergistic and antagonistic drugs.
1) Over dose :-
Rx

Codeine phosphate 0.5 gms

Make powders.
Send such 10 powders.

Overcome:-

It is a unintentional incompatibility

This is the example of overdose medication.
The prescription should be referred back to prescriber for
necessary correction.
2) Drug interaction:-
Rx
Tetracycline Hydrochloride 250 gms

Directions for Pharmacist:

Make Capsules.
Send 10 such capsules.
Label:
Take 10 capsules every six hours with milk.

Overcome:-

Avoid administration of tetracycline with milk to prevent the

formation of insoluble complex.

2) Drug interaction:-
Rx
Acetophenitidin 150 gms
Acetyl salicylic acid 200mg
Caffeine 30mg
Directions for Pharmacist:
Send 10 such capsules.

Overcome:-

Acetophenitidin & Acetyl salicylic acid are analgesics.

Acetophenitidin depresses the CNS and this side effect is undesirable.

Caffeine is CNS stimulant to neutralize the effect of acetophenitidin.

This incompatibility is intentional, so dispense the prescription as such.

3) Synergism:-
1.Aspirin & Paracetamol increases analgesic activity
2.Penicillin & streptomycin increases antibacterial activity.
Rx
Amphetamine Sulphate 20 mg
Ephedrine Sulphate 100 mg
Simple syrup up to 100 ml.
Make a mixture.

Overcome:-
Both are sympathomimetic drugs cause additive effect. Hence of individual drugs dose
should be reduced to avoid the therapeutic incompatibility.

Otherwise the prescription should be referred back to the prescriber for necessary
correction.
3)Antagonism:-
Rx
Aspirin
Probenecid

Overcome:-

Both are anti-gout agents. But upon prescribing them

together there is a neutralization effect.
Hence prescription should be referred back to the
prescriber for necessary correction.
4) Wrong drug or dosage form:-

Certain drugs have similar names and there is always a

danger of dispensing the wrong drug.
For example: 1.prednisone & prednisolone
2.Digoxin & digitoxin
Sometimes many drugs are available in different
dosage form and hence if the dosage form is not clearly
mentioned on prescription,it becomes necessary to seek
clarification from prescriber.
5) Contraindicated Drugs:-

1.Penicillin & sulphonamides are not prescribed for those

patients who are allergic to it.
2.Corticosteroids are never prescribed in peptic ulcer
condition
3.The drugs which will excrete into milk are never
prescribed in lactating mothers.
e.g. Phenytoin, Phenobarbitone, chloramphenicol etc.