Pharmaceutics Department
Pharmaceutical Dosage Forms (1)
Introduction (The
composition of suspension)
Formulation of
Pharmaceutical Suspensions
Requirements of
pesticide active ingredients and solvent
The fundamental
characteristics of suspended emulsions
The fundamental
characteristics of suspended emulsions
Critical micelle
concentration
The physical
stability of the suspended emulsion
The advantages and
disadvantages of Suspended Emulsion
The choice of
surfactant
Physical properties
of a well-formulated suspension
Features Desired In
Pharmaceutical Suspensions
Stability
Packing
Pharmaceutical
applications of suspensions
As
oral DDS
Suspensions
for Topical administration
Suspensions
for parenteral use
Reconstitutable
suspensions
Suspensions
for inhalation
Conclusion
Reference List
Introduction:-
The
composition of suspension
Suspension-emulsion is a new formulation,
which allows the greatest possible to put several incompatible active
ingredients combined to a single formulation. In particular, one or several
water-insoluble liquid pesticide active ingredient (or low melting point
pesticide active ingredient in the solvent mixture) mix with another one or
several water-insoluble solid pesticide active ingredient, with water as
medium, relying on surface-active agent processed into a stable suspended
emulsion formulations. The most popular formulation is prepared by two
different active ingredients in pesticides (ie, a water-insoluble liquid
pesticide active ingredients and the other a water-insoluble solid pesticide
active ingredients) combined to suspended emulsion. Such formulations are
generally composed by three-phase:
1-solid dispersed and suspended particles form the
suspended phase
2-liquid emulsion oil droplets form the emulsion
phase
3-water is the continuous phase. Accordingly,
the dispersed oil phase of emulsion can be composed by different forms, either
by the containing no active ingredient emulsion (for example, containing only
mineral oil or vegetable oil, etc.), or by the containing active ingredients EC
or oil in water of emulsion (micro-emulsion and water emulsion), which can
obtain various forms of suspended emulsion. If there is a water-soluble
pesticide active ingredient (eg, Glyphosate) adding to the aqueous phase, may
also constitute another mixing suspended emulsion.
Surface Active Agents form a unique class of chemical compounds.
This review provides anintroduction to the nature and physical properties of
surfactants, emphasizing theirability to radically alter surface and
interfacial properties and to self-associate andsolubilize themselves in
micelles. These properties provide the means to applysurfactants in wettability
modification, detergency, and the displacement of liquidphases through porous
media on one hand, and to stabilize dispersions (includingfoams, froths and
emulsions), or to destabilize dispersions (again including foamsand emulsions)
on the other hand. These in turn lead to a vast array of practicalapplication
areas which are illustrated in terms of mineral and petroleum processing,biological systems, health and personal
care products, foods, and crop protection.The surfactant industry is dominated
by several types: alkylbenzene sulfonatesalcohol ethoxylates, sulfates and
ethersulfates These are the major components oflaundry detergents, household,
and personal care products and account for over halfof all use of surfactants.
Interest in increasing performance in these areas has also ledto research into
mixed surfactant systems. Other commercial interests have also influencedthe
developments in surfactant science.
For the need of a stable suspension, the
term ‘Structured vehicle’ is most important for formulation view and stability
criteria. The main disadvantage of suspension dosage form that limits its use
in the routine practice is its stability during storage for a long time. To
overcome this problem or to reduce it to some extent, the term ‘Structured
vehicle has got importance
What do you mean by Structured
Vehicle?
The structured vehicle is the vehicle in
which viscosity of the preparation under the static condition of
very low shear on storage approaches
infinity. The vehicle behaves like a ‘false body’, which is able to maintain
the particles suspended which is more
or less stable
Let it be clear that ‘Structured
vehicle’ concept is applicable only to deflocculated suspensions, where hard
solid cake forms due to settling of solid particles and they must be
redispersed
easily and uniformly at the time of
administration. The Structured Vehicle concept is not applicable to flocculated
suspension because settled floccules get easily redispersed on shaking
Generally, concept of Structured vehicle is
not useful for Parenteral suspension because they may create problem in
syringeability due to high viscosity
In addition,
Structured vehicle should possess some degree of Thixotropic behaviour viz.,
the property of GEL-SOL-GEL transformation. Because during storage it should be
remained in the form of GEL to overcome the shear stress and to prevent or
reduce the formation of hard cake at the bottom which to some extent is
beneficial for pourability and uniform dose at the time of administration
Preparation Of Structured Vehicle
Structured vehicles are prepared with the
help of Hydrocolloids. In a particular medium, they first hydrolyzed
and swell to great degree and increase
viscosity at the lower concentration. In addition, it can act as a ‘Protective
colloid’ and stabilize charge.
Density of structured vehicle also can be increased by;
PolyvinylpyrrolidonePolyethylene glycols
Glycerin Sugars
1-Solid and liquid active ingredients in pesticides must be insoluble or
low-solubility in the water (solubility of pesticide active ingredient in
water, generally at the 0 ~ 40 ℃ condition,
preferably less than 500 mg / L. If the solubility in water is too large, then
there is more difficulties to get a stable suspend emulsion formulation.)
2-Solid pesticide
active ingredients must not intersoluble with the liquid pesticide active
ingredient (or low melting point pesticide active ingredient in the solvent
mixture), otherwise the suspend emulsion formulation can not be obtaind.
3-Better to use
liquid pesticide active ingredients, reducing the low melting point pesticide
active ingredient in solvent mixture.
4-Pesticide active
ingredients in the chemical are stable (without decomposition in water).
The
factors must be considered in the selection of solvent or solvent system are
1-The active ingredients of the pesticide have an excellent
solubility
22-The solvent should not dissolve in water or a
low solubility in water (at least less than 0.1%). The solution obtaind should
be stable during the production and storage at all the temperatures (no
crystallization).
3- The solvent has a
high flash point to ensure itssafety during oil phase preparation.
The
fundamental characteristics of suspended emulsions :-
It is very important to provide a stable solid
dispersion in the suspended emulsion. But when produce a stable emulsion using
various methods, the most complicating factor is how to make a stable emulsion
phase. The emulsion phase is unstable thermodynamically system, so there are a
lot of work around how to get non-flocculating or avoid emulsion phase
oil-based competition in the solid dispersions to obtain a stable emulsion
phase. Usually the most used emulsion during processing is oil in water
emulsion (EW) emulsion phase. Therefore, someone view the formulation as a
combination of suspended emulsion SC (SC) and water emulsions (EW)
formulations. It should be noted that simply mixing SC and EW formulations
usually do not obtain a stable suspension emulsion, because the surfactant
(emulsifier and dispersing agent) cannot achieve a right balance system, which
may lead surfactant preferential adsorption on the surface of oil droplets or
dispersed particle surface so that will also cause flocculation miscellaneous
problems, resulting in suspension-emulsion instability.
Critical
micelle concentration
Surface active agent physico-chemical
properties
The physico-chemical properties of surfactants vary
markedly above and below the cmc value.2–8,12,13,16,19,51,67–69,74–82
Below the cmc value,the physico-chemical
properties of ionic surfactants like sodium dodecyl sulfate, SDS,e.g., conductivities,
electromotive force measurements) resemble those of a strongelectrolyte. Above
the cmc value, these properties change dramatically, indicating ahighly
cooperative association process is taking place. This is illustrated by
Preston’s 83 classic graph,The cmc is also of interest because at
concentrations above this value the adsorptionof surfactant at interfaces
usually increases very little. That is, the cmc frequentlyrepresents the
solution concentration of surfactant from which nearly maximumadsorption occurs
The general way of obtaining the cmc value of a surfactant micelle is to
plot anappropriate physico-chemical property versus the surfactant
concentration andobserve the break in the plot.
The physical stability of the suspended emulsion
How to solve the physical stability of the suspended emulsion during
storage is a very important issue, but also is the main problems of restricting
the development and production of the formulation. During storage especially in
the higher temperatures the formulation exist instability: stratification and
sedimentation; separation of solid particles and oil droplets; oil droplets
coalescence; flocculation of solid particles and oil droplets; larger of the
solid particles and oil droplets crystallization (ie, Ostwald ripening); phase
transfer. It is very difficult to get the best suspension emulsion product.
Because not only have to consider two separate formulations (suspension agent
and emulsion phase) may be unstable issues, such as egation as well as poly-and,
Ostwald ripening that is the crystallization of particles and droplets growing
up, hierarchical, milk analysis or deposition, etc. The so-called mixing
flocculation is the flocculation between solid particles and oil droplets, when
a combination of the two dispersion phase. In other words, when one solid
particle is wetted by another oil droplet, the surface-active agent may be
consumed in oil - water interface; if the solid particle is wetted by several
oil droplets, the emulsion coalescence may occur. As the solid particles plays
a catalytic role, which can also accelerate the speed of emulsion coalescence,
ultimately lead to formulation instability.
The advantages and disadvantages of Suspended
Emulsion:-
Suspended Emulsion combine solid and liquid pesticide active ingredients
in the same formulation. The biological effectiveness can complete and expand
prevention and treatment spectrum. Exempt tank mix incompatibility and improve
efficiency. With water as the medium, it is safe to the operator and user,
favorable to environmental protection and cost savings, reducing skin and eye
irritation and toxicity, fewer solvents and avoiding the production of
flammable, explosive and toxic issues. It is easy to use, and low cost of
package, storage and transportation, reducing spray frequency. But it also has
some disadvantages, such as more difficulty to develop high-quality stable
formulations, very high technical requirements for processing and sometimes use
high-shear, homogeneous and other special equipment. There are still packager
washing and treatment problems.
The choice of surfactant:-
Surface-active agents
(emulsifiers, wetting agent and dispersing agent) are fundamental components of
the suspended emulsion, which plays an important role of stability during the
preparation of formulation and long-term storage.
The role of emulsifiers include
1-Lowering the
oil / water surface tension, so that the oil phase emulsify and disperse in the
aqueous phase
2-provide the
electrostatic and space stability between oil droplets (preventing
flocculation, cohesion and coalescence
3-Improve the compatibility
of emulsion and suspension solution in state of concentrated and diluted
The roles of
wetting agent / dispersing agent includes
1-wet the particle surface of
solid active ingredients
2-help wet grinding
3-allow solid particles to disperse in the
continuous phase
4-improve the compatibility of suspension at the
state of concentration and dilution.
The surface-active agents used in suspended emulsion generally selecte
the emulsifier and dispersing agents used in the preparation of SC and EW formulations.
The emulsifiers commonly used are alkyl benzene sulfonates, alkyl phenol
polyoxyethylene ether, styrene phenol polyoxyethylene ether, polyol fatty acid
esters and their polyoxyethylene adduct etc., while nonionic or anionic
compound are used widespread. The dispersants commonly used are lignin
sulfonate, alkyl naphthalene sulfonate formaldehyde condensate, alkyl aryl
polyoxyethylene ether and its phosphate or salt, and EO / PO block copolymer
and so on.
However, to obtain high-quality suspension emulsion, we can choose a
non-reversible adsorption of the polymer surfactant, such as comb-type
copolymers. It is firmly adsorbed on the surface of solid particles and will
not de-absorption and transfer, so that establish a stable dispersion system
and avoid flocculation problems produced in suspension emulsions, obtaining a
stable suspension emulsion. With a silicon of the polymerizable surfactant to
stabilize the O / W emulsion, it can also be a stable suspension emulsion,
which is at the surface of oil droplets exist strong surface anchoring and
strong space exclusion. Wetting solid particles effective protected are
unlikely to occur. At this time, it will not contribute to the coalescence of
emulsion and can get a stable suspension emulsion. In addition, PEO comb – type
and block copolymer used in the hanging emulsion, it is useful for the
stability of the composition of the suspended solids particles
Physical properties of a
well-formulated suspension :-
-Remain
sufficiently homogenous at least at period of shaking the container &
removing the required dose
Sediment formed
on storage must be easily resuspended by moderate shaking-
Viscosity must
not be so high so to be easily removed & applied-
-Suspended
particles must be small & with uniform size to have smooth & elegant
product
Features Desired In Pharmaceutical
Suspensions
The suspended
particles should not settle rapidly and sediment produced, must be
easily re-suspended by the use of moderate amount of
shaking.
It should be easy to
pour yet not watery and no grittiness.
It should have pleasing odour, colour and palatability.
Good syringeability.
It should be physically,
chemically and microbiologically stable.
Parenteral/Ophthalmic
suspension should be sterilizable
STABILITY
One area that has
presented a number of problems includes the assurance of stability of oral
liquid products throughout their expiry period. For example, there have been a
number of recalls of the vitamins with fluoride oral liquid products because of
vitamin degradation. Drugs in the phenothiazine class, such as perphenazine,
chlorpromazine and promethazine have also shown evidence of instability. Good
practice for this class of drug products would include quantitation of both the
active and primary degradant. Dosage form manufacturers should know and have
specifications for the primary degradant. Review the firm's data and validation
data for methods used to quantitate both the active drug and degradant
Because interactions of products with closure systems
are possible, liquids and suspensions undergoing stability studies should be
stored on their side or inverted in order to determine whether contact of the
drug product with the closure system affects product integrity
Moisture loss which
can cause the remaining contents to become superpotent and microbiological
contamination are other problems associated with inadequate closure systems
PACKAGING
Problems in the packaging of oral liquids have
included potency (fill) of unit dose products, accurate calibration of
measuring devices such as droppers that are often provided. The USP does not
provide for dose uniformity testing for oral solutions. Thus, for unit dose
solution products, they should deliver the label claim within the limits
described in the USP. Review the firm's data to assure uniformity of fill and
test procedures to assure that unit dose samples are being tested.
Another problem in the packaging of Oral Liquids is
the lack of cleanliness of containers prior to filling. Fibers and even insects
have been identified as debris in containers, and particularly plastic
containers used for these products. Many manufacturers receive containers
shrink-wrapped in plastic to minimize contamination from fiberboard cartons.
Many manufacturers utilize compressed air to clean containers. Vapors, such as
oil vapors, from the compressed air have occasionally been found to present
problems. Review the firm's systems for the cleaning of containers.
Pharmaceutical
applications of suspensions :-
As
oral DDS
Useful
for people having difficulty in swallowing solid dosage forms
Useful
for drugs that are required to be in a finely divided form in the GIT to poses
high surface area. E.g. Kaolin,
magnesium carbonate& trisilicate to adsorb toxins
Highly
palatable & so suitable for children. E.g.
Paracetamol is available both in solution and as suspension, suspension
is more palatable for children
E.g. Vibramycin®
Monohydrate(doxycycline monohydrate) for Oral Suspension
Vibramycin is an antibacterial drug synthetically
derived from oxytetracycline, and is available as Vibramycin Monohydrate
(doxycycline monohydrate); Vibramycin Hyclate and Vibra-Tabs (doxycycline
hydrochloride hemiethanolate hemihydrate) and Vibramycin Calcium (doxycycline
calcium) for oral administration
Suspensions
for Topical administration
They can be fluid preparations,
e.g. Calamine lotion
Or semisolid preparations with high
conc. Of powder dispersed usually in a paraffin base, e.g. pastes
Also powdered drug may be suspended
in an emulsion base, e.g. Zinc cream
Taclonex (calcipotriene hydrate and
betamethasone propionate) for Topic adm®E.g.
Apply Taclonex®
Topical Suspension to affected areas once daily for up to 8 weeks. Treatment
may be discontinued earlier, if cleared
.
Instruct patients not to exceed a maximum weekly dose of 100 g
Instruct patients to shake bottle prior to using
Taclonex® Topical Suspension and to wash their hands after applying the product
Taclonex® Topical Suspension is not for oral,
ophthalmic, or intravaginal use.
Suspensions
for parenteral use
Useful in
controlling the rate of drug absorption
Useful in
controlling the duration of activity by varying the size of dispersed particles
of the drug
If the drug is
suspended in a Fixed oil such as arachis or sesame, the drug will remain after
injection in the form of drug depot (the release of drug from aqueous vehicle
will be faster.
E.g. ®Methylprednisolone acetate
injectable suspension
is an
anti-inflammatory glucocorticoid for intramuscular, intra-articular, soft
tissue or intralesional injection. It is available as single-dose vials in two
strengths: 40 mg/mL; 80 mg/mLethylprednisolone acetate injectable suspension
USP contains methylprednisolone acetate USP which is the 6-methyl derivative of
prednisolone. Methylprednisolone acetate USP is a white or practically white,
odorless, crystalline powder which melts at about 215° with some decomposition.
It is soluble in dioxane, sparingly soluble in acetone, in alcohol, in
chloroform, and in methanol, and slightly soluble in ether.
Reconstitutable
suspensions
reach user as a mixture of dry powders dispersed in
vehicle (usually water) i.e., reconstituted immediately before use
-
Once reconstituted,
they have limited shelf-lives (weeks)
-
Used for unstable
drugs
E.g.
Dry
powder of pediatric antibiotics can stay for long shelf-life, but when
formulated as suspension used for 15 days
Drug resinate 12.0 gXanthan gum 0.2 gAvicel RC591** 1.5
gSodium saccharin 0.3 gSorbic acid 0.2 gSodium methyl hydroxyl benzoate 0.12
gSodium propyl hydroxyl benzoate 0.08 gPeppermint flavor 0.5 gTitanium dioxide
0.2 gSorbitol powder 20 g______________________________________ *containing 25%
w/w ranitidine base equivalent **mixture of 89% w/w microcrystalline cellulose
and 11% w/w sodium carboxymethylcellulose
All the powders were blended together using a suitable
mixer for subsequent filling into a 150 ml bottle. At the time of dispensing,
80 ml of potable water is added and the mixture shaken to give 100 ml of
suspension containing 150 mg ranitidine base equivalent per 5 ml
Suspensions
for inhalation
Suitable for drugs unstable in GIT
To give rapid therapeutic effect
E.g. ®Budesonide suspension for
nebulizer – inhalation
It is used to control and prevent symptoms (wheezing
and shortness of breath) caused by asthma. This medication belongs to a class
of drugs known as corticosteroids. It works directly in the lungs to make
breathing easier by reducing the irritation and swelling of the airways.This
medication must be used regularly to be effective. It does not work immediately
and should not be used to relieve sudden asthma attacks. If an asthma attack
occurs, use your quick-relief inhaler as prescribed.OTHER This section contains
uses of this drug that are not listed in the approved professional labeling for
the drug but that may be prescribed by your health care professional. Use this
drug for a condition that is listed in this section only if it has been so
prescribed by your health care professional.This medication may also be used to
treat lung diseases such as bronchitis and emphysema..
Summarize for General Application
of suspensions
Suspension is usually applicable for drug which is
insoluble or poorly soluble.
E.g Prednisolone suspension
To prevent degradation of drug or to improve stability
of drug
E.g. Oxytetracycline suspension
To mask the taste of bitter of unpleasant drug
E.g. Chloramphenicol palmitate suspension
Suspension of drug can be formulated for topical
application e.g. Calamine lotion
Suspension can be formulated for parenteral
application in order to control rate of drugabsorption
Vaccines as a immunizing agent are often formulated as
suspension
E.g. Cholera vaccine
X-ray contrast agent are also formulated as suspension
E.g. Barium sulphate for
examination of alimentary tract
Summary
A
Pharmaceutical suspension is a coarse dispersion in which internal phase is
dispersed uniformly throughout the external phase.
The internal
phase consisting of insoluble solid particles having a specific range of size
which is maintained uniformly through
out the
suspending vehicle with aid of single or combination of suspending agent.
The external
phase (suspending medium) is generally aqueous in some instance, may be an
organic or oily liquid for non oral use.
Suspension
dosage form is a preferred and widely accepted dosage forms for insoluble or
poorly soluble drugs for various therapeutic applications. The suspension
dosage form has long been used for insoluble and poorly soluble drugs for
making oral, topical and parenteral products. Pharmaceutical Suspensions, From
Formulation Development to Manufacturing provides the reader with a broad
overview of suspension drug product technology. Individual chapters in this
book focus on suspension formulation principles, excipients, analysis,
pharmaceutical development, preclinical, clinical and regulatory aspects, as
well as the emerging technology of nanosuspensions as nanomedicine. Various
chapters in the book are written by authors from academia, regulatory agencies
and industries who are experts in their respective fields. The book includes
over 600 bibliographic citations, numerous tables and illustrations.
Pharmaceutical
Suspensions is the only volume to date that systematically follows the
suspension dosage development approach used widely in the pharmaceutical
industries starting with pre-formulation/formulation development, pre-clinical
evaluation and critical characterization method development, continuing to
clinical trial essentials and ending with technology transfer essentials and
regulatory filing guidance.
References :-
Book References:-
-MSA Pharmaceutical Dosage Form 1 Book
-Laurier L. Schramm,*a,b Elaine N. Stasiuk b and D. Gerrard Marangoni c (Surfactants and
their applications)
-R. Leung, M. Jeng Hou and D. O. Shah, in Surfactants in
Chemical/Process Engineering, ed. D. T. Wasan,
M. E. Ginn and D. O. Shah, Marcel Dekker, Suspension relation with SAA
New York, 1988, p. 315-
Web References
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