Pengembangan

Farmasetik Bentuk
Sediaan Semi-Solid
Linda Margata
• Drugs incorporated into semisolids either show their activity on the surface layers of
tissues or penetrate into internal layers to reach the site of action.
• For example, an antiseptic ointment should be able to penetrate the skin layers and reach
the deep - seated infections in order to prevent the growth of microbes and heal the
wound.
• Semisolid dosage forms are also used in nontherapeutic conditions for providing
protective and lubricating functions. Cold creams and vanishing creams are classic
examples of such semisolid preparations.
OINTMENTS AND CREAMS
• Ointments are used to:
1. provide protective and emollient effects on the skin
2. carry medicaments for treating certain topical ailments
3. deliver drugs into eye, nose, vagina, and rectum

• Creams are basically ointments which are made less greasy by incorporation of water.
• Hydrophilic creams contain large amounts of water in their external phase (e.g., vanishing
cream) and hydrophobic creams contain water in the internal phase (e.g., cold cream).
• An emulsifying agent is used to disperse the aqueous phase in the oily phase or vice
versa.
• As with ointments, creams are formulated to provide protective, emollient actions or
deliver drugs to surface or interior layers of skin, rectum, and vagina.
• Creams are softer than ointments and are preferred because of their easy removal from
containers and good spreadability over the absorption site
Bases

• The U.S. Pharmacopeia (USP) classifies ointment bases as:

1. hydrocarbon bases (oleaginous bases),
2. absorption bases,
3. water - removable bases, and
4. water - soluble bases (water - miscible bases).
Hydrocarbon bases

• are made of oleaginous materials.

• They provide emollient and protective properties and remain in the skin for prolonged periods.
• It is difficult to incorporate aqueous phases into hydrocarbon bases.
• However, powders can be incorporated into these bases with the aid of liquid petrolatum.
• Removal of hydrocarbon bases from the skin is difficult due to their oily nature.
• Examples: Petrolatum USP, white petrolatum USP, yellow ointment USP, and white ointment
USP
Absorption bases

• contain small amounts of water.

• They provide relatively less emollient properties than hydrocarbon bases.
• Similar to hydrocarbon bases, absorption bases are also difficult to remove from the skin
due to their hydrophobic nature.
• Examples: Hydrophilic petrolatum USP and lanolin USP
Water - removable bases

• are basically oil - in - water emulsions.

• a large proportion of aqueous phase can be incorporated into water - removable bases
with the aid of suitable emulsifying agents.
• It is easy to remove these bases from the skin due to their hydrophilic nature.
• Examples: Hydrophilic ointment USP
Water - soluble bases

• do not contain any oily or oleaginous phase.

• Solids can be easily incorporated into these bases.
• They may be completely removed from the skin due to their water solubility.
• Examples: Polyethylene glycol (PEG) ointment National Formulary (NF)
• Selection of an appropriate base for an ointment or cream formulation depends on the:
1. type of activity desired (e.g., topical or percutaneous absorption),
2. compatibility with other components,
3. physicochemical and microbial stability of the product,
4. ease of manufacture,
5. pourability and spreadability of the formulation,
6. duration of contact,
7. chances of hypersensitivity reactions, and
8. ease of washing from the site of application.
9. In addition, bases that are used in ophthalmic preparations should be nonirritating and should soften
at body temperatures. White petrolatum and liquid petrolatum are generally used in ophthalmic
preparations.
Preparation and Packaging

• ointments and creams may also contain other components such as stabilizers,
preservatives, and levigating agents
• Usually levigation and fusion methods are employed for incorporating these components
into the base.
• Levigation involves simple mixing of base and other components over an ointment slab
using a stainless steel ointment spatula.
• https://www.youtube.com/watch?v=PZ0EA7M31MA
• A fusion process is employed only when the components are stable at fusion
temperatures.
• https://www.youtube.com/watch?v=d4pp-KaKV3g
• Ointments and creams containing white wax, yellow wax, paraffin, stearyl alcohol, and
high - molecular - weight PEGs are generally prepared by the fusion process.
• Selection of levigation or the fusion method depends on the type base, the quantity of
other components, and their solubility and stability characteristics.
• Oleaginous ointments are prepared by both levigation and fusion processes.
• Roller mills are used for producing large quantities of ointments in pharmaceutical
industries
• Absorption - type ointments and creams are prepared by incorporating large quantities
of water into hydrocarbon bases with the aid of a hydrophobic emulsifying agent.
• Water - soluble or water - miscible agents such as alcohol, glycerin, or propylene glycol
are used if the drug needs to be incorporated into the internal aqueous phase.
• If the drug needs to be incorporated into the external oily phase, mineral oils are used as
the levigating agent.
• If the proportion of aqueous phase is larger, inclusion of additional quantities of
emulsifier and application of heat may be needed to achieve uniform dispersion.
• Care must be taken to avoid excessive heating as it can result in evaporation aqueous
phase and precipitation of water - soluble components and formation of stiff and waxy
product.
• Water - removable ointments and creams are basically hydrophilic - type emulsions.
• They are prepared by fusion followed by mechanical addition approach.
• Hydrocarbon components are melted together and added to the aqueous phase that
contains water - soluble components with constant stirring until the mixture congeals. A
hydrophilic emulsifying agent is included in the aqueous phase in order to obtain stable
oil - in - water dispersion. Sodium lauryl sulfate is used in the preparation of hydrophilic
ointment USP.
• Water - soluble ointments and creams do not contain any oily phase.
• Both water - soluble and water - insoluble components are incorporated into water - soluble bases by
both levigation and fusion methods.
• If the drug and other components are water soluble, they are dissolved in a small quantity of water and
incorporated into the base by simple mixing over an ointment slab.
• If the components are insoluble in water, aqueous levigating agents such as glycerin, propylene glycol,
or a liquid PEG are used. The hydrophobic components are mixed with the levigating agent and then
incorporated into the base. Heat aids incorporation of a large quantity of hydrophobic components
• A wide range of machines are available for the large - scale production of ointments and
creams.
• Each of these machines is designed to perform certain unit operations, such as milling,
separation, mixing, emulsification, and deaeration
• Milling is performed to reduce the size of actives and other additives. Various fluid
energy mills, impact mills, cutter mills, compression mills, screening mills, and tumbling
mills are used for this purpose
• Separators are employed for separating materials of different size, shape, and densities.
Either centrifugal separators or vibratory shakers are used for separation
• Mixing of the actives and other formulation components with the ointment or cream base
is performed using various types of low - shear mixers, high - shear mixers, roller mills,
and static mixers. Mixers with heating provisions are also used to aid in the melting of
bases and mixing of components
• Creams are produced with the help of low - shear and high - shear emulsifiers.
• These emulsifi ers are used to disperse the hydrophilic components in the hydrophobic
dispersion phase (e.g., water - in - oil creams) or oleaginous materials in aqueous
dispersion medium (oil - in - water creams)
• Entrapment of air into the fi nal product due to mixing processes is a common issue in the
large - scale manufacturing of semisolid dosage forms. Various offl ine and in - line
deaeration procedures are adopted to minimize this issue.
• Effective deaeration is generally achieved by using vacuum vessel deaerators.
• https://www.youtube.com/watch?v=dXXHzoB-hhs
• https://www.youtube.com/watch?v=Bsxon_GzEbY&t=84s
https://www.youtube.com/watc
h?v=hHPuT1ch-9U&t=74s
• Various low - and high - shear shifters are used to transfer materials from the production
vessel to the packaging machines.
• In the packaging area, various types of holders (e.g., pneumatic, gravity, and auger
holders), fillers (e.g., piston, peristaltic pump, gear pump, orifice, and auger fillers), and
sealers (e.g., heat, torque, microwave, indication, and mechanical crimping sealers) are
used to complete the unit operations.
• Improper processing, handling, packing, or use of ophthalmic ointments lead to microbial
contaminations and eventually result in ocular infections.
• In general, the empty containers are separately sterilized and filled under aseptic condition.
• Final product sterilization by moist heat sterilization or gaseous sterilization is ineffective
because of product viscosity. Dry - heat sterilization is associated with stability issues.
• Antimicrobial preservatives such as benzalkonium chloride, phenyl mercuric acetate,
chlorobutanol, or a combination of methyl paraben and propyl paraben are included in
ophthalmic ointments to retain microbial stability.
Packaging

• An ideal container should:

1. protect the product from the external atmosphere such as heat, humidity, and particulates,
2. be nonreactive with the product components,
3. be easy to use,
4. light in weight, and
5. economic
• Aluminum tubes with special internal epoxy coatings are commercially available for
improving the compatibility and stability of products.
• Various modified plastic materials are used for making ointment tubes.
• low - density polyethylene (LDPE) are generally soft and flexible and offer good moisture
protection.
• high - density polyethylene (HDPE) are relatively harder but offer high moisture protection.
• Polypropylene containers offer high heat resistance
• polyethylene terephthalate (PET) are transparent and provide superior chemical compatibility
A recent method known
as blow fill sealing
(BFS) performs
fabrication of container,
filling of product, and
sealing operations in a
single stage

https://www.youtube.co
m/watch?v=PhO4v9wT
Wb4

https://www.youtube.co
m/watch?v=60YffAHe
KEk
Evaluation

• Ointments and creams are evaluated for various pharmacopeial and nonpharmacopeial
tests to ascertain their physicochemical, microbial, in vitro, and in vivo characteristics.
• These tests help in retaining their quality and minimizing the batch - to - batch variations.
• The USP recommends storage and labeling, microbial screening, minimum fill, and
assays for most ointments and creams
Packaging and Storage
• The USP recommends packaging and storage requirements for each offi cial ointment and cream.
• Generally collapsible tubes, tight containers, or other well - closed containers are recommended
for packing.
• They are stored in either a cool place or at controlled room temperatures.
• In some cases, special storage conditions are recommended: for example, protect from light,
avoid exposure to excessive heat, avoid exposure to direct sunlight, avoid strong fluorescent
lighting, do not refrigerate, and avoid prolonged exposure to temperatures exceeding 30 ° C.
Minimum Fill
• to compare the weight or volume of product filled into each container with their labeled weight or volume
• helps in assessing the content uniformity of product
• applied only to those containers that contain not more than 150 g or mL of preparation
• The USP recommends that the average net content of 10 containers should not be less than the labeled amount.
• If the product weight is less than 60 g or mL, the net content of any single container should not be less than 90% of the labeled amount.
• If the product weight is between 60 and 150 g or mL, the net content of any single container should not be less than 95% of the labeled
amount.
• If these limits are not met, the test is repeated with an additional 20 containers. All semisolid topical preparations should meet these
specifications
Water Content
• The presence of minor quantities of water may alter the microbial, physical, and chemical
stability of ointments and creams
• Titrimetric methods (method I) are usually performed for determining the water content in
these preparations. Special titration setups and reagents (Karl Fischer, KF) are used in these
determinations.
• The maximum allowable limit of water in ointment preparations varies between 0.5 and 1.0%
Metal Particles
• required only for ophthalmic ointments
• The presence of metal particles will irritate the corneal or conjunctival surfaces of the eye
• The USP recommends that the number of such particles in 10 tubes should not exceed 50,
with not more than 8 particles in any individual tube. If these limits are not met, the test is
repeated with an additional 20 tubes. In this case, the total number of particles in 30 tubes
should not exceed 150, and not more than 3 tubes are allowed to contain more than 8 particles
Leakage Test
• mandatory for ophthalmic ointments, which evaluates the intactness of the ointment tube and
its seal
• Ten sealed containers are selected, and their exterior surfaces are cleaned. They are
horizontally placed over absorbent blotting paper and maintained at 60 ± 3 ° C for 8 h.
• The test passes if leakage is not observed from any tube. If leakage is observed, the test is
repeated with an additional 20 tubes. The test passes if not more than 1 tube shows leakage
out of 30 tubes
Sterility Tests
• Ophthalmic semisolids should be free from anaerobic and aerobic bacteria and fungi
• performed by the membrane filtration technique or direct - inoculation techniques
Microbial Screening
• most of the topical ointments are screened for the presence of Staphylococcus aureus and
Pseudomonas aeruginosa
• In some cases, screening for Escherichia coli, Salmonella species, and total aerobic
microbial counts is recommended by the USP
• preparations meant for rectal, vaginal, and urethral applications are tested for yeasts and
molds
Assay
• The quantity of drug present in a unit weight or volume of ointment or cream is
determined by various methods:
1. Spectrophotometric,
2. titrimetric,
3. chromatographic
In Vitro Drug Release Studies
• conducted to ascertain release of drug from the formulation matrix
• Open - chamber diffusion cells such as Franz cells are used for performing in vitro
studies
In Vivo Bioequivalence Studies
• conducted to establish the biological availability or activity of the drug from a topically applied
semisolid formulation.
• Dermatopharmacokinetic (DPK) studies, pharmacodynamic studies, or comparative clinical trials
are generally conducted to assess the bioequivalence of topical products
• Dermatopharmacokinetic (DPK) studies are applicable for topical semisolid products that contain
antifungals, antivirals, corticosteroids, and antibiotics and vaginally applied products.
• They are not applicable for ophthalmic, otic, and other products that damage stratum corneum.
• DPK studies involve measurement of drug concentrations in stratum corneum, drug
uptake, apparent steady state, and elimination after application of the test product onto
skin.
• Pharmacodynamic (PD) studies are also performed to estimate the bioavailability and
bioequivalence of drugs from topically applied semisolids. Therapeutic responses from
drug products are measured and compared between the test and reference products.
GELS
• Gels are semisolid preparations that contain small inorganic particles or large organic
molecules interpenetrated by a liquid.
• Gels are attractive delivery systems as they are simple to manufacture and suitable for
administering drugs through skin, oral, buccal, ophthalmic, nasal, otic, and vaginal
routes.
• They also provide intimate contact between the drug and the site of action or absorption.
Characteristics

• Gels may appear transparent or turbid based on the type of gelling agent used.
• They exhibit different physical properties, namely, imbibition, swelling, syneresis, and
thixotropy
• Imbibition refers to the uptake of water or other liquids by gels without any considerable
increase in its volume
• Swelling refers to the increase in the volume of gel by uptake of water or other liquids.
This property of most gels is influenced by:
• temperature,
• pH,
• presence of electrolytes, and
• other formulation ingredients.
• Syneresis refers to the contraction or shrinkage of gels as a result of squeezing out of
dispersion medium from the gel matrix.
• Thixotropy refers to the non - Newtonian flow nature of gels, which is characterized by a
reversible gel - to - sol formation with no change in volume or temperature
• https://www.youtube.com/watch?v=OAZtejEuz-k&list=PL84M1Aoalz9cWid4yZBcfj_q7
DQM12A9d&index=4
Classification

• Gels are classified as hydrogels and organogels based on the physical state of the gelling
agent in the dispersion.
• Hydrogels are prepared with water - soluble materials or water - dispersible colloids.
• Organogels are prepared using water - insoluble oleaginous materials
Hydrogels

• Natural and synthetic gums such as tragacanth, sodium alginate, and pectin, inorganic
materials such as alumina, bentonite, silica, and veegum, and organic materials such as
cellulose polymers form hydrogels in water.
• Gums and inorganic gelling agents form gel structure due to their viscosity - increasing
nature.
• Organic gelling agents which are generally high - molecular - weight cellulose polymer
derivatives produce gel structure because of their swelling and chain entanglement
properties.
• The physical strength of the gel structure is based on the:
1. quantity of gelling agent,
2. nature and molecular weight of gelling agent,
3. product pH, and
4. gelling temperature
Organogels

• also known as oleaginous gels

• prepared using water - insoluble lipids such as glycerol esters of fatty acids, which swell
in water and form different types of lyotropic liquid crystals.
• Examples: glycerol monooleate, glycerol monopalmito stearete, and glycerol monolinoleate.

• Waxes such as carnauba wax, esparto wax, wool wax, and spermaceti are used in
cosmetic organogel preparations.
Gelling Agents

• An ideal gelling agent:

1. should not interact with other formulation components
2. should be free from microbial attack
3. Changes in the temperature and pH during preparation and preservation should not alter its rheological properties
4. should be economic,
5. readily available,
6. form colorless gels,
7. provide cooling sensation on the site of application, and
8. possess a pleasant odor
Preparation and Packaging

• Gels are relatively easier to prepare compare to ointments and creams.

• In addition to the gelling agent, medicated gels contain drug, antimicrobial preservatives,
stabilizers, dispersing agents, and permeation enhancers.
• Factors essential to obtain a uniform gel preparation:
1. Order of Mixing
2. Order of Mixing
3. Processing Conditions and Duration of Swelling
4. Removal of Entrapped Air
• Order of Mixing : Ideally the drug and other additives are dissolved in the swelling
solvent, and the swelling agent is added to this solution and allowed to swell.
• Gelling Medium : Purified water is the most widely used dispersion medium in the
preparation of gels. Under certain circumstances, gels may also contain cosolvents or
dispersing agents.
• Processing Conditions and Duration of Swelling : The processing temperature, pH of
the dispersion, and duration of swelling are critical parameters in the preparation of gels.
These conditions vary with each gelling agent
• Removal of Entrapped Air : Positioning the propeller at the bottom of the mixing
container minimizes this issue. Further removal of air bubbles can be achieved by long -
term standing, low - temperature storage, sonication, or inclusion of silicon antifoaming
agents. In large - scale production, vacuum vessel deaerators are used to remove the
entrapped air.
Packaging

• Usually they are packed into squeeze tubes or jars made of plastic materials.
• Aluminum containers are also used when the product pH is slightly acidic.
• In large - scale production, different mills, separators, mixers, deaerators, shifters, and
packaging machines are used. Most of this equipment is similar to those discussed under
ointments and creams
Raw materials are drawn into the
multichamber system of the
homogenizer by vacuum and then
mixed and pumped into the
homogenizing zone. The product
which enters the vessel is mixed,
sheared, and recirculated. All the
entrapped air is removed during the
recirculation. The machine also has
an insulated jacket for controlling the
processing temperature.
Evaluation

• The procedures for minimum fill, microbial screening, sterility, assay, in vitro drug
release, and in vivo bioequivalence are similar to those of ointments and creams.
• Homogeneity and Surface Morphology : The homogeneity of gel formulations is
usually assessed by visual inspection and the surface morphology by using scanning
electron microscopy
• pH : Determination of pH is important to maintain consistent quality. As conventional pH
measurements are difficult and often give erratic results, special pH electrodes are used
for viscous gels.
• Alcohol Content: Alcohol levels in some gel preparations are determined by gas
chromatographic (GC) methods.
• Rheological Studies: Viscosity measurement is often the quickest, most accurate, reliable
method to charactreize gels. It gives an idea about the ease with which gels can be
processed, handled, or used.
• Bioadhesion: This test is performed to assess the force of adhesion of a gel with
biological membranes. The bioadhesive property is preferred for ophthalmic, nasal
buccal, and gastroretentive gel formulations
• Stability Studies:
• Being dispersed systems containing water in their matrix, gels are prone to physical, chemical,
and microbial stability issues.
• Syneresis is a commonly observed physical stability problem with gels. It involves squeezing
out dispersion medium due to elastic contraction of polymeric gelling agents. This results in
shrinkage of gels

• Ex Vivo Penetration: are carried out to examine the permeation of drug from gels
through the skin or any other biological membrane