Notes

A) Suppositories:
It is solid dosage form meant to be inserted into Body cavity like rectum , urethra, vagina,
where they melt or soften to release the drugs and produce their local or systemic effect.
B) Incompatibility:
Drug Incompatibility refers to interactions between two or more substances which lead to
changes in chemical, physical, therapeutic properties of the pharmaceutical dosage form.
C) Ointments:
Ointments are preparations for external use, intended for application to the skin. Typically,
they have an oily or greasy consistency and can appear “stiff” as they are applied to the
skin. Ointments contain drug that may act on the skin or be absorbed through the skin for
systemic action.
D) Creams:
Creams are semi-solid emulsions of oil and water. They are divided into two types: oil-in-
water (O/W) creams which are composed of small droplets of oil dispersed in a continuous
water phase, and water-in-oil (W/O) creams which are composed of small droplets of water
dispersed in a continuous oily phase.
E) Pastes:
Pastes are homogeneous semisolid dosage form contains high conc. Of insoluble powder
substance ( not less than 20%) dispersed in the suitable base. The paste are usually less
greasy, more absorptive & stiffer than ointments.
F) Therapeutic incompatibility:
It is the modification of the therapeutic effect of one drug by the prior concomitant
administration of another. (It is also called drug interactions)
G) Suppository Bases:
 It should melt at rectal temperature (360) or dissolve or disperse in body fluid. For eutectic
mixtures and in tropical climate the melting range of the base should be higher.
 Release medicaments easily.
 Shape should remain intact while handling.
 Non-toxic and non-irritant to sensitive and inflammed mucous membrane.
 It should be stable on storage i.e. it does not change color, odor, or drug release pattern.
H) Liquifaction:
• It means that when two solid substances are mixed together, conversion to a liquid state
take place.
• It happens through the following methods:
1. Formation of liquid mixture: when the solid substance is soluble in another solid
substance which lead to decrease of its melting point and conversion to a liquid in certain
ratios.
2. Exit of crystalline water: By mixing hydrated crystals and dry crystals, crystalline water
diffuse to dry crystals.
Suppository Bases:
Types of suppository bases
1. Fatty bases – they melt at body temperature.
2. Water-soluble or water miscible base – they dissolve or disperse in rectal secretions.
3. Emulsifying bases – they emulsifies small amount of aqueous solution of drug.

FATTY BASES
Example: Theobroma oil (Cocoa butter), Synthetic fats.
Theobroma oil (Cocoa butter)
· It is a yellowish-white solid having chocolate flavor.
· It is a mixture of glyceryl esters of stearic, palmitic, oleic and other fatty acids.

Advantages:
(a) A melting point range of 30 to 36 0C; hence it is solid at normal room temperatures but melts
in the body.
(b) Ready liquefaction on warming and rapid setting on cooling.
(c) Miscibility with many ingredients.
(d) Blandness i.e. does not produce irritation.

Disadvantages:
(a) Polymorphism
Cocoa butter has three polymorphs
a-crystals (unstable, m.p. 200C), b-crystals (stable, m.p. 360C) and g-crystals (unstable, 150C).
When melted and cooled it solidifies in different crystalline forms, depending on the temperature
of melting, rate of cooling and size of the mass. If melted below 360C and slowly cooled it forms
stable b-crystals with normal melting point, but if over-heated it may produce, on cooling, unstable
g-crystals, which melt at about 150C, or a-crystals, melting at about 200C. These unstable forms
eventually return to the stable condition but this may take several days and meanwhile, the
suppositories may not set at room temperature or, if set by cooling, may remelt in the warmth of
the patient’s home.
This lowering of the solidification point can also lead to sedimentation of suspended solids.
Consequently, great care must be taken to avoid over-heating the base when making theobroma
oil suppositories.
(b) Adherence to mould
Because theobroma oil does not contract enough on cooling to loosen the suppositories in the
mould, sticking may occur, particularly if the mould is worn. This is prevented by lubricating the
mould before use.
(c) Softening point too low for hot climates
To raise the softening point, whit beeswax may be added to theobroma oil suppositories intended
for use in tropical and subtropical countries.
(d) Melting point reduced by soluble ingredients
Substances, such as chloral hydrate, that dissolve in theobroma oil, may lower its melting point to
such an extent that the suppositories are too soft for use. To restore the melting point, a controlled
amount of white beeswax may be added.
(e) Slow deterioration during storage
This is due to oxidation of the unsaturated glycerides.
(f) Poor water absorbing capacity
This fault can be improved by the addition of emulsifying agents.
(g) Leakage from the body
Sometimes melted base escapes from the rectum or vagina. This is most troublesome with
pessaries because of their larger size, and therefore, these are rarely made with theobroma oil.
(h) Relatively high cost

Synthetic fats
As a substitute of theobroma oil a number of hydrogenated oils, e.g. hydrogenated edible oil,
arachis oil, coconut oil, palm kernel oil, stearic and a mixture of oleic and stearic acids are
recommended.
[N.B. Synthetic suppositories bases are by hydrogenation and subsequent heat treatment of
vegetable oils such as palm oil and arachis oil. The oils are generally esters of unsaturated fatty
acids. Hydrogenation saturates the unsaturated fatty acids and heat treatment splits some of the
triglycerides into fatty acids and partial esters (mono- and di-glycerides). ]

Advantages of these synthetic fats over theobroma oil:

1. Their solidifying points are unaffected by overheating.
2. They have good resistance to oxidation because their unsaturated fatty acids have been
reduced.
3. Their emulsifying and water absorbing capacities are good. [They usually contain a proportion
of partial glycerides some of which, e.g. glyceryl monostearate, are w/o emulsifying agents and,
therefore, their emulsifying and water absorbing capacity are good.
4. No mould lubricant is required because they contract significantly on cooling.
5. They produce colorless, odourless and elegant suppositories.
Disadvantages:
1. They should not be cooled in refrigerator because they become brittle if cooled quickly.
Certain additives e.g. 0.05 % polysorbate80, help to correct this fault.
2. They are more fluid than theobroma oil when melted and at this stage sedimentation rate is
greater. Thickeners such as magnesium stearate , bentonite and colloidal silicon dioxide, may be
added to reduce this.

WATER SOLUBLE AND WATER MISCIBLE BASES

Glycero-Gelatin base
· This is a mixture of glycerol and water made into a stiff jelly by adding gelatin.
· It is used for the preparation of jellies, suppositories and pessaries. The stiffness of the mass
depends upon the proportion of gelatin used which is adjusted according to its use.
· The base being hydrophilic in nature, slowly dissolves in the aqueous secretions and provide
a slow continuous release of medicament. Glycerogelatin base is well suited for suppositories
containing belladonna extract, boric acid, chloral hydrate, bromides, iodides, iodoform, opium,
etc.
· Depending upon the compatibility of the drugs used a suitable type of gelatin is selected for
the purpose. Two types of gelatins are used as suppository base
(i) Type-A or Pharmagel-A which is made by acid hydrolysis (has isoelectric point between 7 to
9 and on the acid side of the range behaves as a cationic agent, being most effective at pH 7 to 8.
) is used for acidic drugs.
(ii) Type-B or Pharmagel-B which is prepared by alkaline hydrolysis (having an isoelectric point
between 4.7 to 5 and on the alkaline side of the range behaves as an anionic agent, being most
effective at pH 7 to 8 ) is used for alkaline drugs

Disadvantages:
Glycerogelain base suppositories are less commonly used than the fatty base suppositories
because:
(i) Glycerol has laxative action.
(ii) They are more difficult to prepare and handle.
(iii) Their solution time depends on the content and quality of the gelatin and the age of the base.
(iv) They are hygroscope, hence must be carefully stored.
(v) Gelatin is incompatible with drugs those precipitate with the protein e.g. tannic acid, ferric
chloride, gallic acid, etc.

Soap-Glycerin Suppositories
 In this case gelatin and curd soap or sodium stearate which makes the
glycerin sufficiently hard for suppositories and a large quantity of glycerin up to
95% of the mass can be incorporated.
 Further the soap helps in the evacuation of glycerin.
 The soap glycerin suppositories have the disadvantage that they are very
hygroscopic, therefore they must be protected from atmosphere and wrapped in
waxed paper or tin foil.

Polyethylene glycol bases / Macrogol bases (Carbowaxes)

Depending on their molecular weight they are available in different physical forms.
Examples of Macrogol bases:
I II III IV
Macrogol 400 - - 20 -
Macrogol 1000 - - - 75
Macrogol 1540 - 33 33 -
 Macrogol 4000 33 - - 25
Macrogol 6000 47 47 47 -
Water 20 20 - -
By choosing a suitable combination a suppository base with the desired characteristics can be
prepared.
Advantages:
1. The mixtures generally have a melting point above 420C, hence, does not require cool
storage and they are satisfactory for use in hot climate.
2. Because of the high melting point they do not melt in the body cavity, rather they gradually
dissolve and disperse, releasing the drug slowly.
3. They do not stick to the wall of the mould since they contract significantly on cooling.
EMULSIFYING BASES
These are synthetic bases and a number of proprietary bases of very good quality are available,
few of which are described below:
Witepsol
They consist of triglycerides of saturated vegetable acids (chain length C12 to C18) with varying
proportions of partial esters.
Massa Esterium
This is another range of bases, consisting of a mixture of di-, tri- and mono- glycerides of
saturated fatty acids with chain lengths of C11 to C17.
Massuppol
It consists of glyceryl esters mainly of lauric acid, to which a small amount of glyceryl
monostearate has been added to improve its water absorbing capacity.
Advantages of these bases over cocoa butter:
1. Over heating does not alter the physical characteristics.
2. They do not stick to the mould. They do not require previous lubrication of the mould
3. They solidify rapidly.
4. They are less liable to get rancid.
5. They can absorb fairly large amount of aqueous liquids.
Methods of Preparation of Ointment:
Preparation of Ointments
• Incorporation Method / Trituration Method
• Fusion Method
• Chemical Reaction
• Emulsification Method

Incorporation Method / Trituration Method

• Powders pass out from mesh no. 250 or 180 or 125.
• Then apply levigation process with small amt. of base.
• Then add remaining quty. of base.
• Finally add liquid ingredients & mix well.
• E.g Whitfield Ointment

Fusion Method
• When an ointment base contains a number of solid ingredients such as white bees wax, cetyl
alcohol, stearyl alcohol, hard paraffin etc.
• By the fusion method, all or some of the components of an ointment are combined & being
melted together and cooled with constant stirring until congealed.
• Naturally, heat-labile substances and any volatile components are added last when the
temperature of the mixture is low enough not to cause decomposition of volatilization of the
components.
Chemical reaction
• Ointment containing free iodine
Iodine is slightly soluble in most of the fats & oil but very readily soluble in conc. Aq.solution of
potassium iodide due to formation of molecular complex.
• These polyiodides complex are readily soluble in water, alcohol & glycerin.
• E.g. Strong iodine ointment is used to treat ringworm in cattle. At one time this type of ointment
used on humans for counter-irritants but they were not popular bec. they remain stain on skin a
deep red colour.
• Ointment containing combined iodine
• Fixed oils & many vegetable & animal fats absorb iodine which combines with the double
bounds of the unsaturated constitutes. Oleic acid + iodine = di-iodo stearic acid
• Since free iodine is not available, these ointments are dark, greenish black in colour & it leaves
no stain on skin when rubbed so, its known as nonstaining iodine ointment.
• E.g. Non-stating iodine ointment.
Emulsification Method
• In this method, fats, oils & waxes are melted on water bath at 700C.
• Then in another beaker take water soluble ingredients with water& heat at same temperature.
• Then, aq. solution are slowly added in melted bases with continuous stirring until product cools
down & semi-solid not be formed.

A) 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.
It is the modification of the therapeutic effect of one drug by the prior concomitant administration
of another. (It is also called drug interactions)
• Mechanisms of therapeutic incompatibility
They are divided into two groups:
1. Pharmacokinetics: involve the effect of a drug on another from the point of view that includes
absorption ,distribution , metabolism and excretion.
2. Pharmacodynamics are related to the pharmacological activity of the interacting drugs e.g
synergism.antagonism, altered cellular transport, effect on the receptor site.
a. Additive effect-occurs when two or or more drugs having the same effect are combined and the
result is the sum of the individual effects relative to the doses used. This additive effect may be
beneficial or harmful to the client.
b. Synergistic effect- occurs when two or more drugs, with or without the same overt effect, are
used together to yield a combined effect that has an outcome greater than the sum of the
singledrugs active components alone
c. Potentiation-describes a particular type of synergistic effect-a drug interaction in which only
one of two drugs exerts the action that is made greater by the presence of the second drug.
d. Antagonistic-reactions have the opposite effect of synergism and result in a combined effect
that is less than either active component alone. (eg. Protamine administered as an antidote to
anticoagulant action of heparin)
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.
B) Chemical Incompatibility:
  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.
a. 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)

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.
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 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.

A) Various Excipients used in the preparation of Semisolid Preparations:

• Bases
• Preservative
• Humectants
• Antioxidants
• Emulsifier
• Gelling agent
• Permeation enhancer
• Buffers

Bases:
• It is one of the most important ingredient used in formulation of semisolid dosage form.
Ointment bases do not merely act as the carriers of the medicaments, but they also control
the extent of absorption of medicaments incorporated in them.
Ideal Properties of Bases:
They should be:
• Inert, non-irritating and non-sensitizing.
• Compatible with skin pH and the drug.
• Good solvent and/or emulsifying agent.
• Emollient, protective, non-greasy and easily removable.
• Release medicament readily at the site of application.
• Pharmaceutically elegant and possess good stability.
ANTIOXIDANTS
Oxygen is a highly reactive atom that is capable of becoming part of potentially damaging
molecules commonly called “free radicals.” Free radicals are capable of attacking the healthy cells
of the body, causing them to lose their structure and function. To prevent this an antioxidants are
added. E.g. Butylated hydroxy anisole, Butylated hydroxy toluene.
PERMEATION ENHANCERS
• Skin can act as a barrier. With the introduction of various penetration enhancers, penetration of
the drug through the skin can be improved.
• E.g. Oleic Acid
EMULSIFIER
• An emulsifier (emulgent) is a substance that stabilizes an emulsion by increasing its kinetic
stability. - Must reduce surface tension for proper emulsification. - Prevents coalescence. - Ability
to increase the viscosity at low concentration.
HUMECTANT A humectant is a hygroscopic substance, Humectants are used to :
• increase the solubility of the active ingredient
• To elevate its skin penetration.
• elevate the hydration of the skin.
BUFFERS
Buffers are added for various purpose such as : - Compatibility with skin. - Drug solubility. - Drug
stability. - E.g. sodium acetate, sodium citrate, potassium metaphosphate.