Formulation of suppositories Flashcards
What are the different types of suppositories (3)
- rectal
- vaginal
- urethral
What are the formations of suppositories (5)
- Different types
- Different shapes and sizes
- Usually between 1-4g
- Drug content varies widely – 0.1% to 40%
- Vehicle (base) in which drug is incorporated – sometimes contains other additives
What is the release process of drugs from suspension suppositories (5)
- Suppository enters
- Melting and spreading
- Sedimentation
- Wetting
- Dissolution
What factors affect the drug release process (5)
- Temperature
- Contact area
- Release medium
- Movements
- Membranes (physiological)
What are the physiological factors affecting absorption from the rectum (4)
- Quantity of fluid available
- Properties of rectum mucus
- Contents of the rectum
- Motility of the rectal wall
What are the properties of the ideal suppository base (6)
- Innocuous.
- Devoid of physiological activity.
- No local irritation.
- Not absorbed through rectal mucosa.
- Neutral (no interaction with actives).
- Rapid/complete fusion, disintegration and dissolution.
How does the time interval between fusion and solidication of the final mixture affect suppository bases (2)
- Time interval between fusion and solidification of final mixture should be sufficiently long to allow filling of mould without difficulty.
- It should also be short enough to prevent sedimentation of suspended solids.
How do fats affect the suppository base (5)
- Most fats have a broad melting range.
- Fats used as suppository bases melt within a 3ºC range.
- Narrow melting range is important in controlling melting time after insertion as well as for maintaining shape under various ambient temperatures
- Onset of melting too low = cannot remove from package.
- Onset above 37ºC = little drug release.
How does formulation affect the suppository base (2)
- should be adaptable for manufacture by either fusion or compaction.
- High-speed manufacture means that contraction on cooling should be sufficient to allow easy release from the mould without the need for a mould lubricant.
How does the final product affect the suppository base (2)
- should be odourless and opaque with a uniform surface.
- It should retain its hardness and fusion point over the range of temperatures at which it is likely to be stored.
Calculate the quantities required to make 15 suppositories each containing 150mg Hamamelis Extract and 560mg Zinc Oxide. Use a 2g mound. Calculate for 18. DV Hamamelis = 1.5. DV Zinc Oxide = 4.7
150mg x 18 suppositories = 2700mg (2.7g)
560mg x 18 suppositories = 10080mg (10.08g)
No. x Mass of supp - ((mass of Ing’t)/(DV of Ing’t))
18 x 2g - (2.7 / 1.5) + (10.08 / 4.7)
36 - (1.8 + 2.14)
36 - 3.94
= 32.06
What is the natural base of rectal drug administration (5)
- All naturally derived suppository bases used today are produced from Cocoa Butter.
- Fatty bases are the most frequently used suppository bases.
- These bases melt at body temperature.
What are Gelatin, Agar, and Waxes bases (2)
- employed as suppository bases and are NOT fatty bases.
- uses are limited and often relegated to special applications because special problems are encountered with their use.
What is theobroma oil (5)
- Solid fat expressed from roasted seeds of Theobroma cacao Linn. (Sterculaceae).
- Defined in most pharmacopoeias.
- 73% mono-oleo-disaturated glycerides (mainly oleo-palmitostearin, linoleic acid).
- Small amounts of saturated acids + traces of sterols.
- Think of it as a mixture of C16 - C18 saturated and unsaturated fatty acid triglycerides
How does the fusion point affect theobroma oil (3)
- Fusion point: 31 - 35ºC, brittle below 25ºC.
- Brittleness is affected by actives and excipients or fats incorporated to improve physical stability, drug release or absorption.
- Must be stored in cool dark place in block or pellet form to prevent rancidity, aerial oxidation and product deterioration.
How does the BP affect theobroma oil (7)
- controls free acid
- controls total ester content
- controls degree of unsaturation
- controls specific gravity
- controls refractive index.
- Solubility test in organic solvents excludes beeswax, stearin and tallow.
- Free fatty acid solidification range must lie within 45-50ºC.
What makes theobroma oil popular (5)
- natural origin
- readily available
- innocuous (not harmful or offensive)
- bland
- nonreactive.
What are the 4 polymorphic forms of theobroma oil (5)
- Gamma - melting point = 18.9℃
- Alpha - melting point = 23℃
- Beta-1 - melting point = 28℃
- Beta - melting point = 34.5℃
- Heating above 38ºC converts to alpha or gamma.
What are the advantages of theobroma oil (4)
- Readily liquefies on heating but sets rapidly when cooled down
- Melts at body temperature
- Miscible with many ingredients
- Bland -no irritation occurs.
What are the disadvantages of theobroma oil (7)
- Polymorphic -it solidifies in a different crystalline form.
- Shrinks slightly on cooling, and adheres to the mould.
- Has a relatively low melting point, making it unsuitable for use in hot climates.
- Deteriorates on storage
- Prone to oxidation.
- Variable quality from batch to batch
- It can be expensive.
How does theobroma oil adhere to moulds (3)
- Only slight contraction on cooling, thus theobroma oil prone to mould adhesion.
- Moulds must therefore be lubricated with: spirit soap, mineral oil, silicone spray or hydro-alcoholic spray.
- MAIN REASON FOR USING SYNTHETIC BASES FOR INDUSTRIAL MANUFACTURE
What is the issue with fat and immiscible liquids
Fat does not emulsify with immiscible liquids (water, glycerol etc) thus emulsifiers may be required.
What emulsifiers may be used to emulsify fat (7)
- Wool fat
- wool alcohols
- cholesterol
- polysorbates
- glyceryl monostearate
- triethanolamine
- emulsifying wax.
What thickeners are used when emulsifying fat (3)
- acacia
- alginates
- gelatin.
How does theobroma oil risk fusion (2)
- Physical stability requirements at elevated temperatures experienced in the tropics cannot be met unless theobroma oil is mixed with beeswax, paraffin wax or cetostearyl alcohol (all confer emulsifying properties).
- Also required if fat-soluble ingredients lower m.pt by forming eutectic mixtures.
What is used to ensure theobroma oil doesn’t risk fusion (6)
- beeswax
- paraffin wax
- cetostearyl alcohol
- Phenol
- chloral hydrate
- volatile oils.
How is theobroma oil decomposed (6)
- Phase separation
- crystallization
- fat rancidification (irritant)
- microbial
- spoilage may result after prolonged storage of emulsified suppositories.
- Preservatives and antioxidants may be added to improve stability.
What is the issue with fragility and theobroma oil (2)
- Cocoa butter is brittle and is unsuitable for high-speed manufacture.
- Fragility may be overcome by the addition of 2% glyceryl monostearate.
How does drug release affect suppositories (4)
- Suppositories usually liquefy within minutes, however, drug may not be released from solution or suspension.
Consider:
- drug solubility characteristics
- oil-water partitioning
- ability to cross intestinal mucosa.
What are hard fats (5)
- Chemically they are usually derivatives of fatty acids that undergo chemical alteration (transesterification) to enhance their use for this application
- Such chemical reactions yield a range of products with controllable characteristics making them suitable to be used as suppository bases.
- For example, hydrogenation is typically carried out to enhance the stability to oxidation and increase chemical inertness. Suitable vegetable oils would include Palm kernel oil and Cottonseed oil.
- Melting point ranges can be more precisely tailored to specific requirements.
- These bases are produced from vegetable fats and oils that are chemically modified during their manufacture
What are the physical characteristics of hard fats (6)
- Mono-, di- or triglycerides of saturated straight-chain fatty acids (C10 to C18).
- White or pale yellow
- brittle
- almost odourless and tasteless solid
- oily to the touch
- Hydroxyl value indicates hydrophilicity.
What are examples of semisynthetic suppository bases (4)
- Suppocire
- Witepsol
- Novata
- Wecobee brands.
What are the different grades of Suppocire suppository bases (5)
A - melting point = 35-36.5℃
B - melting point = 36-37.5℃
C - melting point = 38-40℃
D - melting point = 42-45℃
Grade D is useful if the drug forms a eutectic mixture. Available with and without surfacant
What are the different grades of Suppocire suppository bases (4)
H - for mass production but brittle if fast cooled. H12 (32-33.5℃) used to lower high m.pt. Low hydroxyl range
W - Good for large/small scale. Fast cooling without brittleness. Medium hydroxyl range
S - Good dispersing capacity for drugs, S55 used for high-density powders. High hydroxyl range
E - All melt above 37℃. Useful for raising low m.pt.
What are the advantages of synthetic bases (3)
- The base is more flexible and not brittle.
- More stable on oxidation and hydrolysis.
- Less irritant compared with other bases.
What are the disadvantages of synthetic bases (5)
- The viscosity of the melted synthetic fats is lower than Oil of Theobroma oil
- Greater sedimentation risk of the active ingredients during the preparation process
- Lack of uniformity of the active ingredients
- Can become very brittle if cooled too rapidly, so should not be refrigerated during preparation
- There is more than one grade of synthetic fatty base.
What are water-soluble and water-miscible bases (2)
- Glyco-gelatin
- Macrogols
What is glycogeletin (6)
- These bases are a mixture of glycerol (glycerin) and water stiffened with gelatin.
- Mass of Glycerol suppositories BP has 14% w/w gelatin and 70% w/w glycerol.
- In hot climates, gelatin content can be increased to 18%.
- Gelatin is a purified protein produced by the hydrolysis of the caliginous tissue of animals such as skins and bones.
- Two types of gelatin: Type A(porcine)and Type B (bovine)
- Better drug-release properties than fatty bases
What are the disadvantages of a glycogeletin base (5)
- Glycerol-gelatin base is a mild local irritant, this is useful if a laxative effect is required but otherwise is undesirable. (Soap is occasionally added to enhance the physiological effect. )
- Difficulties in preparation and handling, making it unsuitable for high-speed manufacture.
- Dissolution time depends on the content and quality of the gelatin and also the age of the suppository
- Hygroscopic and therefore require careful storage
- Microbial contamination is more likely than with the fatty bases.
What are macrogols (3)
- These are polyethylene glycols (PEGs) and are permitted for use if soluble in water and body fluids.
- Base dissolves in rectal contents, and so rectal fluid volume can significantly affect time taken for a drug to be released, with greater variability than other types of bases
- Combining different polymers permits modification of drug release times, as well as the brittleness of the base
What are polyethylene glycols (PEGs) blended together to produce suppository bases which vary in (4)
- Melting point.
- Dissolution rates.
- Physico-chemical characteristics.
- Useful for certain drugs e.g. morphine and sulphathiazole.
What are the advantages of macrogol bases (5)
- No physiological effect and complete dissolution within 60 minutes
- Not prone to microbial contamination
- Some polymers have a high melting point
- High water-absorbing capacity
- In solution, viscosity is high, which means there is less likelihood of leakage from body
What are the disadvantages of macrogol bases (5)
- Hygroscopic hence require careful storage
- Brittle if cooled too quickly and may become brittle on storage
- Crystal growth occurs with some active ingredients
- Slightly irritant
- Incompatible with several drugs and materials, e.g. benzocaine, penicillin and plastic
What is an insoluble hydrophobic base
hydrogels
What are hydrogels (6)
- Hydrogels are defined as macromolecular networks that swell, but do not dissolve, in water.
- An example is polyhydroxyethylmethacrylate (pHEMA)
- Swelling (the absorption of water) is a result of the presence of hydrophilic functional groups attached to the polymeric network
- Aqueous insolubility results from the cross-links between adjacent macromolecules
- Drugs are dispersed within the hydrogel matrix, then dried simultaneously immobilising the drug
- On entering an aqueous environment e.g. the rectum, the hydrogel matrix swells allowing the for diffusion-controlled modified drug release
What is an example of an engineered device
Alzet® Minipump
What is a Alzet® Minipump (3)
- Commercially available as unloaded devices.
- Polymeric container, can incorporate almost any drug.
- Drug release is diffusion controlled.
What are the methods of suppository production (3)
- Compression.
- Injection.
- Melting.
What is the injection process of suppository production (3)
- The PEGs are first melted and mixed in a vessel equipped with a stirrer and a heating device at about 60°C to 80°C.
- Additional viscosity -plasticity –adjusting ingredients, auxiliary ingredients, and actives are added while stirring.
- Once blending is complete, the melt is extruded into precision-machined multi-cavity moulds.
Rapid solidification of the melt is followed by the ejection of the moulded units from the mould cavities.
What are the advantages of the injection process of suppository production (3)
- Very fast
- Precise metering and molding
- Range of shapes and sizes
What in-process control is there for suppository production (3)
- Proper monitoring of product physical characteristics is necessary to ensure that the production process remains under control throughout filling.
- Examination of physical defects of finished suppositories provides valuable information for process monitoring.
- Colour variations, chips, cracks, depressions, and surface irregularities are evidence of problems that require attention.
What physical analysis is there for suppository production (4)
- Visual Evaluation.
- Surface appearance and colour can be verified visually to assess:
- Absence of fissuring, pitting, fat blooming, exudation, and migration of the active ingredients.
- The last test accomplished by taking a longitudinal section of the suppository to verify the homogeneity of the active ingredients within the mass.
What melting point analysis is there for suppository production (2)
- The melting point is a critical factor in the determination of the release rate of the active ingredients from the suppository.
- The melting point of the finished suppository should generally not be greater than 37°C.
What liquefaction time analysis is there for suppository production (3)
- This is an important element indicates the physical behavior of a suppository subjected to its maximum functional temperature 37°C.
- It measures the time necessary for a suppository to liquefy under pressures similar to those found in the rectum (30g) in the presence of water at body temperature.
- A rule of thumb is that liquefaction time should be no longer than 30 minutes.
What mechanical strength analysis is there for suppository production (2)
- This is the determination of the mechanical force necessary to break a suppository, and it indicates brittleness or elasticity.
- The mechanical strength should in no case be less than 1.8 to 2 kg
What are the most commonly used methods are melting and solidification analysis is there for suppository production (5)
- Open capillary tube.
- U-Tube.
- Drop Point.
- All require the introduction of a sample into a specified place in the apparatus, after which heat is applied in a controlled manner.
- Means are provided for the determination of the point at which the test material undergoes a change in physical state, (i.e., melts).
What chemical analysis is there for suppository production
This is dependent on the drug involved.
What packaging and storage is there for suppositories (5)
- Plastic (PVC) or aluminium foil pack
- Protection against moisture and oxygen
- Store in cool place
- High humidity – absorb moisture – spongy
- Low humidity – lose moisture - brittle
What are the distinct purposes of rectal retention fluids (2)
- Local-acting liquids intended to be used as bowel evacuants (purgatives - used pre-operatively).
- Retention enemas from which systemic drug absorption is intended.
What are the advantages of retention enemas (3)
- Useful alternative to suppositories and may enable controlled-release of drugs (e.g. by using ion-exchange resins.
- May enhance drug absorption because liquid is applied over a larger area of mucosa cf.. suppositories.
- Thickening agents (e.g. starches and cellulose ethers) aid retention and may render formulation bioadhesive.
What are the uses of retention enemas (2)
- antibacterial lavage (Sodium phthalylsulphathiazole)
- removal of threadworms (quassia infusion).
What are the disadvantages of retention enemas (3)
- Inconvenience.
- Unpleasantness.
- Increased risk of loss by involuntary expulsion - particularly by debilitated and young patients.
