Industrial Pharmaceutical Technology-Birzeit University

Pharmaceutical Technology 2 / MIPT645

SUPPOSITORIES
Laboratory experiment

By: MAYSOUN BALI

Supervisor: DR.HANI SHTAYA
 Suppositories:
The suppositories could be composed of different APIs dissolved or dispersed in an
appropriate base. Which could be solubilised or dispersed in a fatty bases (melting) or water-
soluble bases (dissolving).
Lipophilic drugs are usually integrated into hydrophilic bases while water soluble
drugs are integrated into the fatty base suppositories. When fatty base are used the
melting should take a place immediately at body temperature, and readily diffuses to
cover the rectum surface.
The base of suppositories:
1- Should be inert, nontoxic, compatible, easily compressed in the mould, readily
release the drug, non-absorbable and stable upon heating and storage.
2- Classified as hydrophilic bases, oleaginous bases and miscellaneous bases
combining both hydrophilic and hydrophobic bases.
3- The APIs preferred to be dissolved in the base not dispersed to overcome the
issue of partition coefficient between the base and the rectum fluids.
4- The base could be hard fat, cocoa butter, water and glycerol, gelatinous
mixtures or macrogols.
For sustained release suppositories, HPMC and Glyceryl Behenate polymer could be
used. Multiple excipients are used, surfactants preferred to be non-ionic, lubricants,
antimicrobial preservatives and colouring agents.
Main parameters for drug absorption from suppositories:
 Melting point of base (lipid base).
 The rate of melting of lipid base.
 Rate of solubility of water base.
 Viscosity: if not enough can cause sedimentation of the mixture and affect the
integrity of the final product.
 Dissolution rate: influenced by the surfactant used, solubility, viscosity,
particle size of API.

Fatty bases
Cocoabutter Advantages: It satisfies the requirements for an ideal base – innocuous, bland, and non-reactive, and melts at
(theobroma body temp
oil)
Disadvantages: Polymorphism, Adherence to mould, Low softening point, Melting point reduction,
Deterioration during storage, Poor water absorbing capacity and Leakage from the body.
Synthetic fats Advantages: Their solidifying points are unaffected by over heating. They have good resistance to oxidation
because their unsaturated fatty acids have been reduced. The difference between melting and setting points is
 small; generally only 1.5 to 2C˚ and seldom over 3C˚. They set quickly, the risk of sedimentation is low and
they are easier to administer. The melting point depression caused by fat soluble drugs can be counteracted by
choosing a high melting point grade, while the hardness and brittleness that sometimes results from a high
content of insoluble powder can be prevented by using a low melting point grade. W/o emulsifying agents, No
mould lubricant is needed because they contract significantly on cooling, have very attractive, clean and
polished appearance.
Disadvantages: They should not be cooled in a refrigerator or ice because they become brittle if cooled
quickly. Additives such as polysorbate 80 correct this fault. They are more fluid than theobroma oil when
melted and at this stage sedimentation is greater. Thickeners such as magnesium stearate, bentonite reduce
this problem.
proprietary Whitepsol (formerly called Imhausen), Massa Estarinum and Massuppol.
synthetic
bases/ Advantages: No polymorphism, Tolerance of oxidation, Rapid Solidify, Do not need mould lubricant, Mix
Emulsifying with physiological fluid easily, non-irritant, withstand overheating and can absorbs large amount of aqueous
bases liquids.
Disadvantages: Should not be cooled in refrigerator or on ice, Become brittle if cooled quickly, They may
have dehydrating effect and problems with API sedimentation due to low viscosity on melting and more
expensive.
Water soluble or water miscible bases
glycero- Advantages: dissolves in body secretions and therefore is preferable to a fatty base for administering
gelatin antiseptics. Since, solution is slow; drug release is more prolonged than from fatty base. At present, the B.P
allows a maximum disintegration time of 1 hr. for Glycerol Suppositories B.P made with gelatine of B.P
standard.
Disadvantages:  They have a physiological action (used as laxative) They are more difficult to prepare and
handle. Their solution time depends on the content and quality and gelatin and the age of the base. They are
hygroscopic. So a careful storage is required. It also leads to dehydration of the rectal mucosa with consequent
irritation; this is an advantage where a laxative effect is required. Gelatin is incompatible with protein
precipitants such as tannic acid.
macrogols Advantages: The mixtures have melting point above 42C˚, cool storage is not required, they are satisfactory
(PEG) for use in hot climates, and administration is easy because they are not slippery to handle. Do not melt in the
body but gradually dissolve and disperse, freeing their medication slowly and providing longer action than
fatty bases. Their physical properties can be varied by suitable admixture of high and low polymers. High
polymers give hard products that disintegrate and release their drug slowly. Softer, less brittle preparations
that disperse and liberate their drug more quickly are obtained by mixing high with either medium or medium
and low polymers or by adding plasticizers.
They do not stick to the mould since they contract on cooling. Because of their high molecular weight solution
of high viscosity are produced when they disperse in the body. They absorb water well and have excellent
solvent properties. Products have clean smooth appearance

Disadvantages:  They are hygroscopic so careful storage is required. Irritancy can be reduced by
incorporating about 20% of water in the mass or by instructing the patient to dip the preparation in water just
before insertion. This type of base is suitable for systemically active drugs. Its good solvent properties can
result in retention of the drug in the liquefied base in the body with consequent reduction in therapeutic
activity. Products sometimes fracture on storage, particularly if they contain High solubility of macrogols
which can lead to a super saturated solution in the water and subsequent crystallisation and this the mass
granular and brittle. Crystal growth of certain medicaments may occur particularly if they are partly in
solution and partly in suspension in the base. This makes the product brittle and crystals may be irritating
because they are large and takes longer time to dissolve. They are incompatible with bismuth salts, tannins
and phenol. They lower the activity of some antibacterial agents and dissolve certain plastics necessitating
care in choosing containers.

Experiment .1- Formula

Table 1.(10 suppositories).
Suppositories base classification and characterisation.
materials weight Function Melting solubility description
point
1 10
supp supp
Paracetamol 0.1g 1g Analgesic 169C˚ Soluble in boiling Nonsteroidal Anti-inflammatory
(acetaminophen) (pain relievers) water, freely Drug, hepatotoxic in overdose
and antipyretic soluble in alcohol,
(fever reducers slightly soluble in
). ether and insoluble
in petroleum ether.
Witepsol   1.3g 13g Emulsifying/ 33.5C˚ Lipophilic material They consist of triglycerides of
synthetic base to soluble in saturated vegetable fatty acid
35.5C˚ petroleum, spirit, with varying percentage of
acetone, methylene partial esters. They have 20
chloride, ether and different grades with hydroxyl
hot isopropanol. It values between 20–50. Consist
is insoluble in of mixture of 65–80% of
water, ethanol, triglycerides, 10–35% of
glycerol and diglycerides and 1-5% of
polyethylene monoglycerides. The most
glycol. available grade for pharmacist is
Witepsol H15.
It represent fast solidification
time and can easily remove from
the mould. However, have a
problem when removed from the
mould resulting in breakage of
suppository into pieces,
lubrication is required, and It
should not be cooled rapidly as
it become brittle and fracture. A
small amount of beeswax is
added for use in hot climate.
Weight of the 1st SUPP = 2.44 / weight of 2nd SUPP =3.70
Table 2. Materials description
Notes on witepsol base:
1- Witepsol hydroxyl value: the quantity (mg) of KOH needed to neutralize the quantity
of acetic acid utilized while acetylation by 1 g of witepsol. It express the total amount
of free hydroxyl groups in the suppository base.
2- Monoglycerides and diglycerides in witepsol can affect the quality of the fatty base
and the suppositories. Can affect the crystallization and plasticity. Can raise the
viscosity of the mix. Act as surfactants.
3- Witepsol H15 is recommended for large scale production while witepsol 45 suitable
for small scale dispensing.
4- Advantages of witepsol: no need for mould lubrication, unaffected by the heat, the
partial glycerides in witepsol base act as water in oil emulsifying agents and enables a
good amount of aqueous solutions to be incorporated.
5- Suppositories made with witepsol base should not be cooled rapidly as it become
brittle and fracture.
6- They are suitable for formulation of eutectic mixtures and tropical suppositories. E.g.
Witepsol H 15 disintegrates almost as fast in the rectum as cocoa butter. The melting
times were 4 minutes for cocoabutter, 6 minutes for Witepsol.
Challenges in suppository preparation:
1- Cracks: are created by forces in the solid fat, which appears from a varies cooling
degrees at the surface and within the mould. To avoid these damages ■ choosing an
elastic fat ■ decreasing the total temperature and raising the cooling temperature, for
more homogeneous fat solidification. Cross cracks can also be created by mechanical
 stress of the solidifying, for example in the enclosing process, when excessive mould
filling and high pressure is applied.
2- Matt surface: fat buds on the surface when the crystalline fat diffuses on the surface.
Rare phenomena in fat have low contraction that does not produce a gap between the
surface and the packing foil. To avoid this problem use compound with low
contraction or recrystallized fats.
3- Sedimentation or inhomogeneous distribution of APIs : this might be related to low
viscosity of the melt or large particle size, to solve the problem ■ lower the
temperature of the mix ■ raise the cooling upon ejection ■ use viscosity enhancer e.g.
Aerosil, 2% aluminium monostearate, cetyl and stearyl alcohols may be added to
improve consistency ■ reduce particle size ■ reduce the density differences between
the drug particles and the base.
4- Solidification of the mixture: Poor solidification especially in high dose of API that
form gel like mass with the base. This might be related to the dissolution of API by
glyceride constituent of witepsol. The solution are ■use witepsol grade with low
hydroxyl value ■ use API with different range of particle size
■ use viscosity lowering excipients e.g. Lecithin.
The effect of emulsifier in suppositories base:
Up on preparation: They act as water absorption capacity of fatty base and enables
suppositories containing aqueous active-principle solutions to be prepared. It can also reduce
agglomeration by wetting the drug powder.
After administration: Emulsifiers can be used to effectively disperse lipophilic material and
drugs in the primarily aqueous point of delivery, by forming micelles or stabilizing small
droplets (enhance spreading of the base on the mucosal surface). It can also increase the rate
of drug release from the base.
 The emulsifier is preferably present in a quantity of 0.2 to 10% by weight.
 E.g. of emulsifiers Poly sorbates (tween 61, tween 80), Wool alcohol and Wool fats
sorbitan ester (span).

Exp2- Suppository with PEG Base

PEGs

 are available in a variety of molecular weight ranges

 A long chain polymer known by its trade name Carbowax.
 Have the advantage of allowing the formulation of many degrees of freedom in that
the ratios of the low to the high molecular weight.
  The lower the molecular weight of the PEG, the higher the hydrophilicity, the higher
hydroxyl value as compared to higher molecular weight PEG
 Depending upon their chain length and molecular weight, PEGs range:
 being a clear colourless liquid (PEG 300–PEG 600)
 A wax-like white solid (PEG 1450, PEG 3350, PEG 8000).
 Various combinations of PEGs combined by fusion, using two or more of the various
types to achieve a suppository base of the desired consistency and characteristics.
 The mixture of PEG400 and PEG 4000 produce softer, less brittle preparations that
disperse and liberate their drug more quickly
 PEG base suppositories do not melt at body temperature but rather dissolve slowly in
the body’s fluids. Thus, suppositories from mixtures prepared having melting points
considerably higher than body temperature to permits a slower release of the
medication from the base , and permits convenient storage of these suppositories
without need for refrigeration .
 PEG base suppositories do not leak from the orifice because they mix with mucous
secretions upon their dissolution.

Ingredients Percentage Weight

Paracetamol 5% 0.815g
Ingredient Percentage Weight 15.485g
Base PEG 400 40%
95%
6.52g
PEG 4000 60% 9.78g

Calculation of the amounts required:

Theoretical weight =
20g-----------------------------------------------------------------------------------Weight of empty
beaker = 73.7 g. ------------------------------------------------------------------------Weight of one
SUPP base without API (1.7g.) ---------------------------------------------------------Weight of tow
SUPP base without API (3.70g)-------------------------------------------------------Determine the
amount of base required:-------------------------------------------------------------Weight of base
required = (theoretical weight – weight of base displaced)*base %

(20 – 3.7)*95% = 15.485g

Determine the amount of API required:

Weight of API required = (theoretical weight – weight of base displaced)*API %

(20 – 3.7)*5% = 0.815g

 Questions

Q1- what is the effect of PEG6000 when used instead of PEG4000?

 PEG600 is higher MW (higher content of hydroxyl groups within the structure).
Polymer, which give harder SUPP that, permits a slower disintegration and release of
the medication from the base.
  PEG6000 SUPP would have clear white in colour, very hard, lack of greasy
(less hydrophopic than PEG4000) but are insoluble in water as time taken for the
melting of suppositories is longer.
 The SUPP with the PEG 4000 is more opaque while suppositories with PEG6000 is
more transparent.
 PEG6000 SUPP are less hygroscopic, easier to store and handle.

Q2- Describe the effect of different bases on the physical characteristic of the
suppositories?

base shape texture greasiness color

Witepsol bullet hard No greasiness Dark white

Cocoabutter bullet Soft, sticky very greasy Dark white

(theobroma oil)

PEG 4000 bullet Hard and smooth greasy Clear

white

PEG 400 bullet Soft and greasy greasy white

 Two important factors when preparing suppositories with cocoa butter base.
 This base must not be heated above 35°C (95°F) because cocoa butter is a
polymorphic compound and if overheated will convert to a metastable structure that
melts in the 25° to 30°C (77° to 86°F) range. Thus, the finished suppositories would
melt at room temperature and not be usable.
 The change in melting point caused by adding certain drugs to cocoa butter
suppositories. For example, chloral hydrate and phenol tend to lower the melting
point. It may be necessary to add spermaceti or beeswax to raise the melting point of
finished suppositories back to the desired range.

 Witepsol suppositories base.

 H15 grade is the most readily available to pharmacists. It has a melting point
range of 33.5°C to 35.5°C, which is quite close to its congealing range of
32°C to 34°C.
 Suppositories made with this base solidify rapidly and should contract to
release easily from the mould, there are reports of problems with
suppositories breaking into pieces when being removed from the suppository
mould.

 PEG suppository bases.

 They are formulated so they do not melt at body temperature but rather
dissolve in body fluids. Suppositories made from these bases should be
moistened with water before insertion.
 Because their melting points are easily controlled by appropriate blending,
these bases and their suppositories do not require carefully monitored storage
temperatures
  When formulated with an appropriate PEG blend, they dissolve in body
cavity fluids and release the active ingredient(s), both hydrophilic and
hydrophobic drugs. There are sufficient aqueous secretions in the body
cavity; they provide more reliable release of drug from the dosage form than
do fatty bases.

Suppositories of cocoa butter Witepsol suppositories base PEG suppositories base

cocCocoabutter

Suppositories I II III

PEG 6000 0 3 9
amount (g)

Shape

Bullet
Bullet Bullet
 
   

Translucent
Colour Off-White Clear white
white

Hardness + ++ +++

Greasiness         +++ ++ +

Table 3. A study of the effect of different amount of PEG6000 on the physical characteristics
of suppositories.