Integrated Paharmaceutics II

CUC Integrated Pharmaceutics II Lecture Note ͟͢͠͞
Chapter one: Semisolid dosage forms

STRUCTURE, FUNCTION AND TOPICAL
TREATMENT OF HUMAN SKIN
The skin combines with the mucosal linings of the urogenital, digestive and respiratory tracts to
protect the internal body structure from a hostile external environment of varying pollution,
temperature, humidity and radiation. The skin safeguards the internal organs, limits the passage
of chemicals into and out of the body, stabilizes blood pressure and temperature, and mediates
the sensations of heat, cold, touch and pain. It expresses emotions (such as the pallor of fear, the
redness of embarrassment and anger, and the sweating of anxiety). The integument identifies
individuals through the characteristics particular to humans, e.g. colour, hair, odour and texture.
Skin damages easily: mechanically, chemically, biologically and by radiation. Thus the tissue
suffers cuts, bruises, burns, bites and stings; detergents, chemical residues, organic solvents and
pollutants attack and penetrate the surface; and microorganisms and plants deliver contact
allergens. Topical and systemic drugs, toiletries and cosmetics and many diseases may all harm
the skin.
Anatomy and physiology

The human skin comprises three tissue layers: the stratified, avascular, cellular epidermis, the
underlying dermis of connective tissue, and the subcutaneous fat (Fig. 33.1 (a)). Hairy skin
contains hair follicles and sebaceous glands; the glabrous skin of the soles and palms produces a
thick epidermis with a compact stratum corneum, but there are no hair follicles or sebaceous
glands.
The epidermis
The multilayered epidermis varies in thickness, ranging from about 0.8 mm on the palms and
soles to 0.006 mm on the eyelids. The cells of the basal layer (stratum germinativum) divide and
migrate upwards to produce the stratum corneum or horny layer. Humans survive in a non-
aqueous environment because of the almost impermeable nature of this dead, dense layer, which
is crucially important in controlling the percutaneous absorption of drugs arid other chemicals.
The stratum corneum may be only 10 (Jim thick when dry but swells severalfold in water.
There are two main types of horny layer: the pads of the palms and soles, which are adapted for
weight bearing and friction, and the remaining flexible, rather impermeable membranous layer.
The basal cell layer also includes melanocytes, which produce and distribute melanin granules to
the keratinocytes. Langerhans' cells (important in defence mechanisms operated by the immune
system) are prominent in the epidermis.
The dermis
The dermis (or coriurri), at 3-5 mm thick, consists of a matrix of connective tissue woven from
fibrous proteins (collagen, elastin and reticulin) that are embedded in an amorphous ground
substance of mucopolysaccharide. Nerves, blood vessels and lymphatics traverse the matrix and
skin appendages (eccrine sweat glands, apocrine glands, and pilosebaceous units) pierce it. The
dermis needs an efficient blood supply to convey nutrients, remove waste products, regulate
pressure and temperature, mobilize defence forces and contribute to skin colour. Branches from
Compiled by: S.G (MSc) Page 1 of 83

the arterial plexus deliver blood to sweat glands, hair follicles, subcutaneous fat and the dermis
itself.
This supply reaches to within 0.2 mm of the skin surface, so that it quickly absorbs and
systematically dilutes most compounds passing the epidermis. The generous blood volume in the
skin usually acts as a 'sink' for diffusing molecules reaching the capillaries, keeping penetrant
concentrations in the dermis very low, maximizing epidermal concentration gradients, and thus
promoting percutaneous absorption.

Fig. 33.1 Simplified diagram of skin structure and routes of drug penetration, (a) Macroroutes:
(1) via the sweat ducts; (2) across the continuous stratum corneum; or (3) through the hair
follicles with their associated sebaceous glands, (b) Representation of the stratum corneum
membrane, illustrating two possible microroutes for permeation.
The subcutaneous tissue

The subcutaneous fat (subcutis, hypoderrri) provides

a mechanical cushion and a thermal barrier; it synthesizes and stores readily available high-
energy chemicals.
The skin appendages

The eccrine sweat glands (2-5 million) produce sweat (pH 4.0-6.8) and may also secrete drugs,
proteins, antibodies and antigens. Their principal function is to aid heat control, but emotional
stress can also provoke sweating (the clammy palm syndrome).
The apocrine sweat glands develop at the pilosebaceous follicle to provide the characteristic
adult distribution in the armpit (axilla), the breast areola and the perianal region. The milky or
oily secretion may be coloured and contains proteins, lipids, lipoproteins and saccharides.
Surface bacteria metabolize this odourless liquid to produce the characteristic body smell.
Hair follicles develop over all skin except the red part of the lips, the palms and soles, and parts
of the sex organs. One or more sebaceous glands, and in some body regions an apocrine gland,
open into the follicle above the muscle that attaches the follicle to the dermoepidermal junction.
Sebaceous glands are most numerous and largest on the face, the forehead, in the ear, on the
midline of the back and on anogenital surfaces; the palms and soles usually lack them. These
holocrine glands produce sebum from cell disintegration; its principal components are
glycerides, free fatty acids, cholesterol, cholesterol esters, wax esters and squalene. Abnormal
sebaceous activity may lead to seborrhea (excess sebum), gland hyperplasia without clinical
seborrhoea, obstruction of the pilosebaceous canal (acne and comedones - whiteheads or
blackheads), and other types of dysfunction - the dyssebacias. The nails, like hair, consist of
'hard' keratin with a relatively high sulphur content, mainly as cysteine. Unlike the stratum
corneum, the nail behaves as a hydrophilic matrix with respect to its permeability.
Rational approach to drug delivery to and via the skin

There are three main ways to attack the problem of formulating a successful topical dosage form:
1. We can manipulate the barrier function of the skin: for example, topical antibiotics and
antibacterials help a damaged barrier to ward off infection; sunscreen agents and the horny layer
protect the viable tissues from ultraviolet radiation; and emollient preparations restore pliability
to a desiccated horny layer.
2. We can direct drugs to the viable skin tissues without using oral, systemic or other routes of
therapy.
3. The third approach uses skin delivery for systemic treatment. For example, transdermal
therapeutic systems provide systemic therapy for conditions such as motion sickness, angina and
pain.
Dermatologists aim at five main target regions: skin surface, horny layer, viable epidermis and
upper dermis, skin glands and systemic circulation (Figs. 33.1 and 33.2).
Surface treatment
We care for the skin surface mainly by using a simple camouflage or cosmetic application, by
forming a protective layer, or by attacking bacteria and fungi. Some examples include protective

films, sunscreens, and barriers that hinder moisture loss and so avert chapping. For topical
antibiotics, antiseptics and deodorants, the surface microorganisms are the target. Then, effective
surface bioavailability requires that the formulation should release the antimicrobial so it can
penetrate the surface skin fissures and reach the organisms. Developmental studies should at
least confirm that the formulation releases and does not bind the medicament.
Stratum corneum treatment

The main therapies aimed at the horny layer improve emolliency by raising water content, or
stimulate sloughing (keratosis) with, for example, salicylic acid. The insertion of moisturizing
agents or kera- tolytics into the stratum corneum involves their release from the vehicle and

penetration into the tissue. Ideally, the medicament should not enter viable skin, but this is
difficult to prevent.
Skin appendage treatment

We may reduce hyperhydrosis of the sweat glands with antiperspirants such as aluminium or
other metal salts. In acne we use topical exfolients such as salicylic acid, tretinoin (retinoic acid)
or isotretinoin, and benzoyl peroxide and antibiotics such as erythromycin and clindamycin.
Other topical antibiotics applied in skin treatment include framycetin and neomycin sulphates,
fusidic acid, polymyxins and mupirocin. Depilatories usually contain strontium or barium
sulphides, or thioglycolates; malepattern baldness may be treated with minoxidil and finasteride.
Topical imidazoles (clotrimazole, econozole, miconazole, ketoconazole and sulconazole),
amoralfine and terbinafme treat fungal diseases of the nails, stratum corneum and hair.
Delivering the medicament to the diseased site is a problem with appendage treatment. For
example, it is difficult to achieve a high antibiotic concentration in a sebaceous gland when, as in
acne, a horny plug blocks the follicle. When delivered through the skin, the drug may not be
sufficiently hydrophobic to partition from the water-rich viable epidermis and dermis into the
sebum-filled gland.
Viable epidermis and dermis treatment

We can treat many diseases provided that the preparation delivers drug to the receptor
efficiently.
However, many potentially valuable drugs cannot be used topically as they do not readily cross
the stratum corneum. Hence, investigators may use stratagems such as adding penetration
enhancers to diminish this layer's barrier function (see later). Another approach develops
prodrugs, which reach the biological receptor and release the pharmacologically active fragment.
The efficacy of many topical steroids depends partly on molecular groups that promote
percutaneous absorption but which may not enhance drug-receptor binding.

Fig. 33.4 Some stages in drug delivery from a transdermal patch. (Modified from Barry (1983),
with permission.)
Drug examples include topical steroidal and nonsteroidal anti-inflammatory agents;

corticosteroids may also be used in psoriasis. Antibiotics include those listed above. Anaesthetic
drugs such as benzocaine,
amethocaine and lignocaine reduce pain, and antipruritics and antihistamines alleviate itch, but
they may cause sensitization. Topical 5-fluorouracil and methotrexate eradicate premalignant

and some malignant skin tumours, and treat psoriasis. The psoralens (particularly in conjunction
with ultraviolet light - PUVA therapy) mitigate psoriasis; and 5-aminolaevulinic acid (with
visible light irradiation - photodynamic therapy) treats skin cancer.
Transcutaneous immunization
The skin has a highly effective immunological surveillance and effector system. A new therapy
involves developing transcutaneous immunization via the topical application of vaccine antigens.
The process uses an adjuvant such as cholera toxin added to a vaccine antigen (e.g. diphtheria
toxoid) to induce antibodies to the diphtheria toxoid. The adjuvant and the antigen target
Langerhans' cells, potent antigen-presenting cells in the epidermis. Simple application of the
vaccine formulation to the skin of experimental animals and human volunteers has produced
positive responses.
Systemic treatment via transdermal absorption

Generally, in the past healthy skin has not been used as a drug route during systemic attacks on
disease, with the noteworthy exceptions of nitroglycerin and antileprotics. The body absorbs
drugs slowly and incompletely through the stratum corneum, and much of the preparation is lost
by washing, by adherence to clothes and by shedding with stratum corneum scales. Other
problems include marked variations in skin permeability with regard to subject, site, age and
condition, which make control difficult. However, in recent years considerable scientific work
has led to the route being used to treat several conditions by means of transdermal patches (see
later).
Figure 33.2 illustrates drug penetration routes and examples of treatments appropriate to various
skin strata.
The fraction of a drug that penetrates the skin via any particular route depends on:
• the physicochemical nature of the drug, particularly its size, solubility and partition
coefficient;
• the timescale of observation;
• the site and condition of the skin;
• the formulation;
• how vehicle components temporarily change the properties of the stratum corneum.
Ideal molecular properties for drug penetration

From the above considerations, we can deduce the ideal properties that a molecule would require
so as to penetrate the stratum corneum well. In brief, these are:
• A low molecular mass, preferably less than 600 Da, when the diffusion coefficient will
tend to be high;
• An adequate solubility in oil and water, so that the concentration gradient in the
membrane can be high;
• A balanced partition coefficient;
• A low melting point; this correlates with good ideal solubility.

These features explain why transdermal patches can deliver adequate amounts of nicotine to be
effective in smoking cessation therapy - this drug illustrates all these requirements well.
Dermatological formulations
Liquid preparations
Liquid preparations for external application include simple soaks or baths, applications,
liniments, lotions, paints, varnishes, tinctures, and ear drops. A simple soak provides an active
ingredient in aqueous solution or suspension, sometimes with water-miscible solvents. Gums and
gelling agents may vary the consistency, from mobile liquids to stiff ringing gels. Bath additives
such as Oilatum Emollient deposit a layer of liquid paraffin on the stratum corneum in an attempt
to maintain its moisture content by occlusion. Applications may be liquid or viscous and often
incorporate parasiticides, e.g. dicophane, benzyl benzoate, gamma benzene hexachloride and
malathion. Liniments may be alcoholic or oily solutions or emulsions, which should not be
applied to broken skin. Lotions are aqueous solutions or suspensions from which water
evaporates to leave a thin uniform coating of powder. Evaporation cools and soothes the skin,
making lotions valuable for treating acutely inflamed areas. Alcohol enhances the cooling effect
and glycerol sticks the powder to the skin. Lotions may also be dilute emulsions, usually of the
oil-in-water type. Paints, varnishes and tinctures present solutions of active ingredients in volatile
solvents such as water, industrial methylated spirits, acetone or ether. Ear drops are often
aqueous solutions, although glycerol and alcohol may also be used.
Gels (jellies)
Gels are two-component semisolid systems rich in liquid. Their one characteristic feature is the
presence of a continuous structure providing solidlike properties. In a typical polar gel, a natural
or synthetic polymer builds a three-dimensional matrix throughout a hydrophilic liquid. Typical
polymers used include the natural gums tragacanth, carrageenan, pectin, agar and alginic acid;
semisynthetic materials such as methylcellulose, hydroxyethylcellulose,
hydroxypropylmethylcellulose and carboxymethylcellulose; and the synthetic polymer Carbopol
(carbomer). Certain clays such as bentonite, Veegum and Laponite may be also used. Provided
that the drug does not bind to the polymer or clay, such gels release medicaments well; the pores
allow relatively free diffusion of molecules that are not too large.
Powders
Dusting powders for application to skin folds are finely divided (impalpable) insoluble powders
which dry, protect and lubricate, e.g. talc, zinc oxide, starch and kaolin. Dusting powders should
not contain
boric acid, as abraded skin may absorb it in toxic amounts.
Ointments
Ointments are greasy, semisolid preparations, often anhydrous and containing dissolved or
dispersed medicaments.
Hydrocarbon bases
These usually consist of soft paraffin or mixtures with hard paraffin. Paraffins form a greasy film
on the skin, inhibiting moisture loss and improving hydration of the horny layer in dry scaly
conditions. This hydration is also a main reason why ointments are so effective in encouraging
percutaneous absorption of a drug.

The Plastibases are a series of hydrocarbons containing polyethylene, which forms a structural
matrix in systems which are fluid at the molecular scale but are typical dermatological
semisolids. They are soft, smooth, homogenous, neutral, colourless, odourless, non-irritating,
non-sensitizing, extremely stable vehicles. Plastibases are compatible with most medicaments
and they maintain their consistency even at high concentrations of solids and under extremes of
temperature. The bases apply easily and spread readily, adhere to the skin, imparting a velvety,
non-greasy feel, and can readily be removed. Soap-based greases may be produced by, for
example, incorporating aluminium stearate in a heavy mineral oil. A random arrangement of
metallic soap fibres weaves throughout the oil, producing a product which changes its
consistency only slightly when heated; the base readily incorporates drugs and the addition of
lanolin permits the absorption of a little water.
Fats and fixed-oil bases Dermatological vehicles have frequently contained fixed oils of
vegetable origin, consisting essentially of the mono-, di- and triglycerides of mixtures of
saturated and unsaturated fatty acids. The most common oils include peanut, sesame, olive,
cottonseed, almond, arachis, maize and persic. Such oils can decompose on exposure to air, light
and high temperatures, and may turn rancid. Trace metal contaminants catalyse oxidative
reactions which the formulator combats with antioxidants, such as butylated hydroxytoluene,
butylated
hydroxyanisole or propyl gallate, or with chelating agents such as the salts of
ethylenediaminetetraacetic acid (EDTA). However, antioxidants may be incompatible with the
drug or they may sensitize some patients.
Silicones Dimethicones, or dimethyl polysiloxanes, have properties similar to hydrocarbon bases.

They are water repellent with a low surface tension and are incorporated into barrier creams to
protect the skin against water-soluble irritants.
Absorption bases Absorption bases soak up water to form water-in-oil emulsions while retaining
their semisolid consistencies. Generally, they are anhydrous vehicles composed of a hydrocarbon
base and a miscible substance with polar groups that functions as a water-in-oil emulsifier, e.g.
lanolin, lanolin isolates, cholesterol, lanosterol and other sterols, acetylated sterols, or the partial
esters of polyhydric alcohols such as sorbitan monostearate or mono-oleate. Bases such as Wool
Alcohols Ointment BP and Simple Ointment BP deposit a greasy film on the skin, similar to a
hydrocarbon base, but they suppress less the transepidermal water loss. However, they may
hydrate the stratum corneum by applying a water-in-oil emulsion, thereby prolonging the time
during which the horny layer can absorb moisture. Some individuals are sensitive to lanolin. This
may be important because the sensitization occurs unexpectedly and physicians frequently
overlook it, especially in atopic patients, who may apply large quantities of lanolin-containing
emollients for protracted periods. Modern purified lanolin preparations are less sensitizing.
Emulsifying bases These essentially anhydrous bases contain oil-in-water emulsifying agents
which make them miscible with water and so washable or 'self-emulsifying'. There are three
types, depending on the ionic nature of the water-soluble emulsifying agents: anionic (e.g.
Emulsifying Ointment), cationic (e.g. Cetrimide Emulsifying Ointment) and nonionic (e.g.

Cetomacrogol Emulsifying Ointment). Because they contain surfactants, emulsifying bases may
help to bring the medicament into more intimate contact with the skin. The bases mix with
aqueous secretions and readily wash off the skin; thus they are useful for scalp treatments.
Water-soluble bases Formulators prepare watersoluble bases from mixtures of high and low
molecular weight polyethylene glycols (macrogols, Carbowaxes). Suitable combinations provide
products with an ointment-like consistency, which soften or melt on skin application. They are
nonocclusive, mix readily with skin exudates and do not stain sheets or clothing; washing
quickly removes any residue. The macrogols do not hydrolyse, deteriorate, support mould
growth or irritate the skin. Examples include Macrogol Ointment and Polyethylene Glycol
Ointment; because they are water-soluble, they will not take up more than 8% of an aqueous
solution before losing their desirable physicochemical characteristics.
To enable a base to incorporate more water stearyl alcohol can be substituted for some of the
macrogol component. Macrogol bases are used with local anaesthetics such as lignocaine, but
they are incompatible with many chemicals, including phenols, iodine, potassium iodide,
sorbitol, tannic acid, and the salts of silver, mercury and bismuth. The bases diminish the
antimicrobial activity of quaternary ammonium compounds and methyl and propyl
parahydroxybenzoates, and rapidly inactivate bacitracin and penicillin.
Creams
Creams are semisolid emulsions for external application. Oil-in-water emulsions are most useful
as waterwashable bases, whereas water-in-oil emulsions are emollient and cleansing. Patients
often prefer a w/o cream to an ointment because the cream spreads more readily, is less greasy,
and the evaporating water soothes the inflamed tissue. O/w creams ('vanishing' creams) rub into
the skin; the continuous phase evaporates and increases the concentration of a watersoluble drug
in the adhering film. The concentration gradient for drug across the stratum corneum therefore
increases, promoting percutaneous absorption.
To minimize drug precipitation, a formulator may include a less volatile, water-miscible

cosolvent. An o/w cream is non-occlusive because it does not deposit a continuous film of water-
impervious liquid. However, such a cream can deposit lipids and other moisturizers on and into
the stratum corneum and so restore the tissue's hydration ability, i.e. the preparation has
emollient properties. It is difficult to predict the role that an emulsion plays in percutaneous
absorption. This is because, added to all the physiological and physicochemical considerations
already discussed, the following must also be considered:
• Partitioning of the medicament between the emulsion phases;
• The addition of preservatives;
• Determination of a true viscosity for the diffusing molecules in the vehicle;
• The possibility of phase inversion or cracking of the emulsion when applied to the skin.
Drug may also be trapped in the micelles and the gel and liquid crystalline phases present in the
continuous phase. Emulsions are complex systems and so all medicaments must be considered

individually with respect to emulsion design. There are few worthwhile formulation guidelines
additional to the principles already discussed.
Pastes
Pastes are ointments containing as much as 50% powder dispersed in a fatty base. They may be
useful for absorbing noxious chemicals in babies, such as the ammonia that bacteria release from
urine.
Because of their consistency, pastes localize the action of an irritant or staining material, such as
dithranol or coal tar. They are less greasy than ointments because the powder absorbs some of
the fluid hydrocarbons. Pastes lay down a thick, unbroken, relatively impermeable film that can
be opaque and act as an efficient sun filter. Skiers use such formulations on the face to minimize
windburn (excessive dehydration) and to block out the sun's rays.
Aerosols
Aerosols may function as drug delivery systems for solutions, suspensions, powders, semisolids
and emulsions. Solution aerosols are simple products with the drug dissolved in a propellant or a
propellant/solvent mixture. Typical agents incorporated are steroids, antibiotics and astringents.
The powder aerosol methodology is useful for difficult soluble compounds such as steroids and
antibiotics. Semisolid preparations, such as ointments and creams, may be prepared in a flexible
bag with compressed nitrogen used for expulsion instead of a volatile propellant. Emulsion
systems produce foams that may be aqueous or non-aqueous and stable or quick-breaking.
Medicinal stable foams are aqueous formulations used, for example, for preoperative shaving
and for= contraception. The stable foam, which is similar to a medicated shaving cream, varies in
stability depending on the surfactant, solvent and propellant used.
Cosmetic or aesthetic criteria for dermatological formulations

However well designed a topical vehicle for maximum drug bioavailability is, the preparation
must still be acceptable to the patient. A product that is poor in appearance may lead to non-
compliance. Patients generally prefer a formulation which is easy to transfer from the container,
spreads readily and smoothly, leaves no detectable residue, and adheres to the treated area
without being tacky or difficult to remove. The dosage of such preparations is typically in the
range of 1-5 mg/cm2 of skin. Stiff pastes may be hard to rub into the skin or to apply evenly;
application to damaged areas may therefore be painful. However, a thick layer of material can
occlude the tissue or protect it from mechanical, chemical or light damage. Ointments and pastes
do this, and the viscous drag imposed on application may dislodge scales, dead tissue and the
remnants of previous doses. The medicament then makes intimate contact with the diseased site.
A stiff preparation also helps to delineate the area of treatment. The sensations of greasiness and
tackiness arise from those constituents that form the skin film. For creams, stearic acid and cetyl
alcohol produce nontacky films. Formulations that include synthetic or natural gums should use
the minimum amount, as the polymers tend to leave a tacky coating on the skin. Insoluble solids
leave an opaque layer that often appears powdery or crusty. However, as therapy requires such
solids in lotions and pastes, the formulator can do little to vary the film's nature and patients
accept the residue as part of the treatment.

Physicochemical criteria for dermatological formulations

The developer of dosage forms must note the physical and chemical behaviour of the drug and
the dosage form during preformulation studies, throughout bench-scale work, pilot studies and
batch processing, at the manufacturing level, and during storage and use of a product. Some
general factors that a pharmaceutical scientist evaluates for a new semisolid during
developmental studies and storage include:
• Stability of the active ingredients
• Stability of the adjuvants
• Rheological properties - consistency, viscoelasticity, extrudability
• Loss of volatiles, including water
• Phase changes - inhomogeneity, bleeding, cracking
• Particle size distribution of dispersed phase
• Apparent pH
• Particulate contamination.
The first difficulty arises in assessing the chemical stabilities of the drug (in its complex vehicle)
and the adjuvants. A general method establishes a shelf-life by using an accelerated stability test
at elevated temperatures and the Arrhenius relationship. However, for a multiphase system such
as a cream, heat may change the phase distribution and may even crack the emulsion. Thus, the
investigator may have to assess the preparation for a long time at the storage temperature.
Because of vehicle complexity, it may be difficult to separate the labile components for analysis.

Chapter Two: SUPPOSITORIES AND PESSARIES/ RECTAL DRUG DELIVERY

Introduction
The administration of drugs by routes other than the oral one has to be considered in several
circumstances and for a great many varying reasons.
Arguments for choosing the rectal route for drug administration include:
1. The patient is not able to make use of the oral route. This may be the case when the
patient have a problem with their gastrointestinal tract, is nauseous or is postoperative
(when they may be unconscious or not able to ingest a drug orally). Furthermore, several
categories of patients, i.e. the very young, the very old or the mentally disturbed, may
more easily use the rectal than the oral route.
2. The drug under consideration is less suited for oral administration. This may be so in
cases where oral intake results in gastrointestinal side effects; also, the drug may be
insufficiently stable at the pH of the GI tract, or susceptible to enzymatic attack in the GI
tract or during the first passage of the liver after absorption. Also, drugs with an
unacceptable taste can be administered rectally without this inconvenience to the patient.
The formulation into suppositories of certain drugs that are candidates for abuse, as in
suicide, has also been considered.
Besides these apparent advantages, the rectal route also has several drawbacks. Depending on
tradition, there are strong feelings of aversion in certain countries, such as the UK and the USA,
to rectal administration of drugs, whereas there is complete acceptance on the continent and in
Eastern Europe. More rational points in this respect are the slow and sometimes incomplete
absorption that has been reported, and the considerable inter- and intrasubject variation. The
development of proctitis has also been reported. There are also problems with the large-scale
production of suppositories and the achievement of a suitable shelf-life (the latter demanding
stringent storage conditions).
It can thus be concluded that rectal administration should certainly not be the route of first
choice, but can in certain circumstances be of great advantage to the patient. The rectal route is
used in many different therapies, intended either for local or for systemic effect. Local effect is
desired in the case of pain and itching, mostly due to the occurrence of haemorrhoids. Locally
active drugs which are used include astringents, antiseptics, local anaesthetics, vasoconstrictors,
anti-inflammatory compounds and soothing and protective agents. Also some laxatives fall into
this category. For the attainment of a systemic effect all orally given drugs can be used and many
are, bearing in mind the limitations discussed above. Antiasthmatic, antirheumatic and analgesic
drugs are very much used for this purpose.
Anatomy and physiology of the rectum

Rectal dosage forms are introduced into the body through the anus and are thus brought into the
most caudal part of the GI tract, i.e. the rectum. Anatomically the rectum is part of the colon,
forming the last 150-200 mm of the GI tract. The rectum can be subdivided into the anal canal
and the ampulla, the latter forming approximately 80% of the organ. It is separated from the
outside world by a circular muscle, the anus. The rectum can be considered as a hollow organ
with a relatively flat wall surface, without villi and with only three major folds, the rectal valves.

The rectal wall is formed by an epithelium which is one cell layer thick, and is composed of
cylindrical cells and goblet cells which secrete mucus. A diagram of part of the rectal wall and
the rectum's venous drainage is shown in Figure 34.1.
The total volume of mucus is estimated as approximately 3 mL, spread over a total surface area
of approximately 300 cm2. The pH of the mucous layer is reported as approximately 7.5.
Furthermore, there seems to be little buffer capacity. This point will be discussed later in relation
to absorption. Under normal circumstances the rectum is empty; filling provokes a defecation
reflex, which is under voluntary control. Data comparing drug absorption from freshly prepared
and aged, more viscous suppositories suggest that there is enough motility to provoke the
spreading even of rather viscous suppositories.
Fig. 34.1 Venous drainage of the human rectum (after Tondury, 1981): 1 middle rectal vein; 2
tunica muscularis: stratum longitudinale; 3 m. levator ani; 4 inferior rectal vein; 5 m. sphincter

ani externus; 6 superior rectal vein; 7 and 8 plexus venosus rectalis (submucosus); 9 skin; 10 v.
marginalis.
Absorption of drugs from the rectum

Blood supply, especially venous drainage, is important for the understanding of drug absorption.
As can be seen from Figure 34.1, there are three separate veins. The lower and middle
haemorrhoidal veins drain directly into the general circulation; the upper one drains into the
portal vein, which flows to the liver. This means that drug molecules can enter the general
circulation directly or by passing through the strongly metabolizing liver. In the latter case only a
proportion of the drug molecules (if they are of the high clearance type) will enter the general
circulation intact. Thus the bioavailability may be less than 100%. Compared to the small
intestine this situation is still more favourable. Recent investigations have shown that avoiding
the first passage through the liver is possible, but the extent of this effect cannot be generalized,
as it will depend on the actual part of the rectum through which the drug is absorbed.
Thus keeping the drug in the lower part of the rectum would be advisable.
The insertion of a suppository into the rectum results in a chain of effects leading to the
bioavailability of the drug. This is represented in a simplified scheme in Figure 34.2.

Depending on the character of its vehicle (see later) a suppository will either dissolve in the
rectal fluid or melt on the mucous layer. Because the volume of rectal fluid is so small,
dissolution of the complete vehicle will be difficult and require extra water. Owing to osmotic
effects (of the dissolving vehicle) water is attracted, with the unpleasant consequence of a painful
sensation for the patient.
Independent of the vehicle type, drugs that are dissolved in the suppository will diffuse out
towards the rectal membranes. Suspended drugs will first have to leave the vehicle (if it is water
immiscible) under the influence of either gravity or motility movements, and can then start
dissolving in the rectal fluid. The dissolved drug molecules will have to diffuse through the
mucous layer and then into and through the epithelium forming the rectal wall.
The process of absorption will be a passive transported back into the colon, depending on the
voluntary control exhibited on the anal sphincter. The rectal wall may exert a pressure on a
suppository present in the lumen by two distinct mechanisms. First, the abdominal organs may
simply press on to the rectum, especially when the body is upright. This may stimulate spreading
and thus promote absorption. The second source of pressure is the motility of the muscles of the
rectal wall, which may originate from the normally occurring colonic motor complexes. These
are waves of contractions running over the wall of the colon in a caudal direction and are
associated with the presence of food residues in the colon.
In contrast with the upper part of the GI tract, in the rectum no esterase or peptidase activity is
present, resulting in a much greater stability of peptide-like drugs. Administration of these
compounds using the rectal or vaginal route has been satisfactory, but only if absorption
enhancers such as surfactants were used concomitantly. All kinds of surfactants seem to do the
promoting work, of which polyoxyethylene lauryl alcohol ether appears to be the most powerful.
One major drawback of these enhancers, however, is the irritation of the rectal mucosa in the
long term; less irritating enhancers are needed to explore this interesting area in greater depth.

Formulation of suppositories
Suppositories are used mainly for the administration of drugs via the rectal route, but not
exclusively.
Application via other routes, such as the vagina, is less common but of distinct use in the
treatment of locally occurring infections. Other suppository-type products (bougies) used
through other body orifices, e.g. the ear, nose and urethra, are very uncommon and are not
discussed here. Alternative dosage forms for the rectal and or vaginal route are tablets, capsules,
ointments and enemas. These will be discussed later, and concentrate first on rectal
suppositories. Suppositories are formulated in different shapes and sizes (usually 1-4 g). Their
drug content varies widely, from less than 0.1% up to almost 40%. A more detailed description,
together with the methods of preparation can be found in Pharmaceutical Practice (Winfield and
Richards 1998). Generally the suppository consists of a vehicle in which the drug is
incorporated, and in some cases additives are coformulated.
The vehicle (suppository base)

There are two main classes of vehicles in use, the glyceride-type fatty bases and the water-
soluble ones. Although the ideal vehicle has not been found, the large variety of bases that are
available enables a well considered choice for every drug that has to be formulated as a
suppository. Choosing the optimum base requires a lot of practical experience and at present this
can only partly be guided by scientifically sound data. Much remains to be learned here.
However, some general guidelines can be given.
Requirements of the vehicle There is no doubt that a suppository should either melt after
insertion in the body or dissolve in (and mix with) the available volume of rectal fluid. For fatty
bases this means a melting range lower than approximately 37°C (one must be aware of the fact
that the body temperature might be as low as 36°C at night).The melting range should be small
enough to give rapid solidification after preparation, thereby preventing the separation of
suspended, especially high-density, drug particles and agglomeration. When the solidification
rate is high this may result in fissures, especially when rapid cooling is applied. On the other
hand, the melting range should be large enough to permit easy preparation, which on an
industrial scale may take a considerable length of time.
During solidification a suppository should exhibit enough volume contraction to permit removal
from the mould or plastic former. The viscosity of the molten base plays an important role both
from a technological and from a biopharmaceutical point of view. During preparation the
viscosity determines the flow into the moulds, but also the separation of drug particles. Clearly a
compromise has to be found here. During and after melting in the rectal cavity the suppository
mass is forced to spread over the absorbing surface, the rate of which may be determined partly
by its viscosity. Drug particles that have to be transported through the base to the interface with
the rectal fluid, and have to pass this interface to be released, will evidently also see viscosity as
a determining factor in their journey.
A good suppository base should further be chemically and physically stable during storage as a
bulk product, and after preparation into a suppository. It should have no incompatibility with
drug molecules and should permit an optimal release of the drug it contains. Clearly this list of

requirements cannot always be completely fulfilled, and often an acceptable compromise is the
best that one can expect.
Fatty vehicles The fatty vehicles in use nowadays are almost exclusively semi- or fully synthetic
ones.
Cocoa butter is no longer used because of its many disadvantages, such as its well known
polymorphic behaviour, its insufficient contraction at cooling, low softening point, chemical
instability, poor waterabsorptive power and its price. The semisynthetic type of fatty vehicles
(sometimes termed adeps solidus) have few or none of the problems mentioned above. A
comparison is made in Table 34.2.
The general composition of both types is mixed triglycerides with C12-C18 acids. In the
semisynthetic vehicles these acids are saturated, whereas cocoa butter contains a considerable
amount of the unsaturated oleic acid (see iodine number in the table, which for reducing drugs
should be <0.5). The presence of oleic acid is almost solely responsible for the special properties
of this vehicle. The melting range of the (semi) synthetic bases is usually approximately 3°C and
higher than that of cocoa butter; the acid content is lower (mostly <0.5), which is one of the
reasons that the ageing of aminophylline suppositories is slower when (semi) synthetic vehicles
are used. The hydroxyl number in the table refers directly to the amount of mono- and
diglycerides present in the fatty base. A high number means that the power to absorb water is
high. This may lead to an increased rate of decomposition for drugs that are easily hydrolysed,
such as acetylsalicylic acid. It should be realized that this capacity could lead to the formation of
a w/o emulsion in the rectum, which is generally to be avoided because of its very low drug
release rate. An advantage of a high hydroxyl number is the larger melting and solidifying range,
which permits easier manufacture.
Water-soluble vehicles Water-soluble (or miscible) vehicles are much less used, for reasons to be
discussed below. They comprise the classic glycerol-gelatin or soap bases, which are used The
macrogols are also used. They consist of mixtures of polyethylene glycols of different molecular
weight. The melting point is well over body temperature, which means that they mix with the
rectal fluid. For true dissolution the available volume of rectal fluid (1-3 mL) is too small.
Because of their high melting point they are especially suited for application in tropical climates,
but several disadvantages must be considered. They are hygroscopic and therefore attract water,

resulting in a painful sensation for the patient. The incorporation of at least 20% water and
moistening before insertion can help to reduce this problem. A considerable number of
incompatibilities with various drugs (e.g. phenols, sulphonamides) has been reported. Owing to
the solubilizing character of this base (low dielectric constant) drugs may tend to remain in the
base and release may be slow.
Choice of vehicle A summary of the points that are important for the choice of a suppository base
is given in Table 34.3. The parameters mentioned are evidently not independent of each other,
and one interesting parameter can be added to this list, i.e. the volume of the suppository.
Usually suppositories for adults are 2 mL and those for children 1 mL. It has been suggested that
the larger volume may provoke a reaction in the rectal wall, thus helping to spread the melt over
a larger area. Indeed the increase in volume of, for example, paracetamol suppositories, resulted
in faster and more complete drug absorption.
Determination of the Amount of Base Required

In the prescription for medicated suppositories to be prepared extemporaneously by the
pharmacist, the prescribing physician indicates the amount of medicinal substance desired in
each suppository but leaves the amount of base to the discretion of the pharmacist. Generally, in
preparing such prescriptions, the pharmacist calculates the amounts of materials needed for the
preparation of one or two more suppositories than the number prescribed to compensate for the
inevitable loss of some material and to ensure having enough material.
In determining the amount of base to be incorporated with the medicaments, the pharmacist must
be certain that the required amount of drug is provided in each suppository. Because the volume
of the mold is known (from the determined volume of the melted suppositories formed from the
base), the volume of the drug substances subtracted from the total volume of the mold will give
the volume of base required. If the added amounts of medicaments are slight, they may be
considered to be negligible, and no deduction from the total volume of base may be deemed
necessary. However, if considerable quantities of other substances are to be used, the volumes of
these materials are important and should be used to calculate the amount of base actually
required to fi ll the mold. The total volume of these materials is subtracted from the volume of
the mold, and the appropriate amount of base is added.
Because the bases are solid at room temperature, the volume of base may be converted to weight
from the density of the material. For example, if 12 mL of cocoa butter is required to fill a
suppository mold and if the medicaments in the formula have a collective volume of 2.8 mL, 9.2
mL of cocoa butter will be required. By multiplying 9.2 mL times the density of cocoa butte


The drug
Table 34.4 lists the factors related to the drug substance that are of possible consequence for the
quality of suppositories.

Drug solubility in vehicle The drug solubility in the vehicle is of particular interest from the
biopharmaceutical point of view, as it directly determines the type of product, i.e. solution or
suspension suppository. The drug solubility in the rectal fluid determines the maximum
attainable concentration and thus the driving force for absorption. When a drug has a high
vehicle to water partition coefficient it is likely to be in solution to an appreciable extent (or
completely) in the vehicle.

This generally means that the tendency to leave the vehicle will be small and so the release rate
into the rectal fluid will be low. This is obviously unfavourable for rapid absorption. On the other
hand, a certain lipid solubility is required for penetration through the rectal membranes (see
above, under Absorption of drugs from the rectum). The optimal balance between these two
requirements is usually found using the rules listed in Table 34.5. This table assumes that the
release from the dosage form is considered as the rate-limiting step. Thus the tendency to remain
in the base should be lowered as much as possible (rules 1 and 2). When the solubility in fat and
water are both low no definite rule can be given. It may well be that the dissolution rate will
become the controlling step, and thus it seems advisable to use micronized drug particles.
Particle size The particle size of the drug is an important parameter, both technologically and
biopharmaceutically. To prevent undue sedimentation during or after preparation the particle size
should be limited. The available literature data do not allow us to define an exact limit; however,
the use of particles smaller than approximately 150 /xm is an indication rather than a rule.
Manufacture
Suppositories are manufactured both on a smallscale in batches of 10-20 and on a
(semi)automatic scale in batches up to 20 000 per hour. Essentially the mode of manufacture is
similar in both cases, and involves melting of the vehicle, mixing the drug and the molten
vehicle, dispensing in a former, cooling to solidify and, if necessary, packing in the final
container. Most suppositories are nowadays packed individually in a plastic (PVC) or aluminium
foil pack. Requirements leading to a good protection against moisture and oxygen can be
deduced from the individual needs of the drug and the properties of the packaging material.

Rectal formulations other than suppositories

Apart from suppositories, many formulations can be used for the rectal administration of drugs.
For the treatment of local disturbances, such as haemorrhoids, fatty ointments are widely used.
In the treatment of rectocolitis large-volume enemas are used, e.g. 100 mL.This enables the drug
to reach the upper part of the rectum and the sigmoid colon.
For the systemic administration of drugs, delivery forms such as tablets, capsules and
microenemas are used. Tablets are not very attractive because they cannot disintegrate rapidly,
owing to the small amount of water present in the rectum. Tablets that release CO2 after
insertion can be used, thereby stimulating defecation. Capsules used to achieve a systemic effect
are usually filled with a solution or suspension of the drug in vegetable oil or paraffin. Such
capsules are mostly of the soft-shell type. Limited experience has been obtained with this dosage
form, but it seems that there are no striking differences between the bioavailability from rectal
capsules and that from fatty suppositories.
Microenemas are solutions or dispersions of the drug in a small volume (approximately 3 mL) of
water or vegetable oil. This form is supplied in a small plastic container equipped with an
application tube. After insertion of the tube, the container is emptied by compressing the bulb.
The advantage of this delivery system is obvious, as no melting and dissolution process is
necessary before drug release can start, if water is used as a vehicle. Many good results have
been obtained with drugs delivered in microenemas, but this form is still of limited applicability
because of its relatively high cost compared to suppositories, for example. Moreover,
administration cannot be performed easily by patients themselves, and it is rather difficult to
deliver the total content of the plastic container.

VAGINAL DRUG DELIVERY

Vaginal administration of drugs
The vaginal route is mainly used for the achievement of local effects, e.g. in the case of
Trichomonas and Candida infections. Some drugs are, however, administered vaginally to
achieve systemic effects. In some cases the drugs given by intravaginal route have a higher
bioavailability than with the oral route, because the drug enters immediately into the systemic
circulation without passing the metabolizing liver (as is the case with drugs absorbed from the
lower part of the rectum).
The vaginal wall is very well suited for the absorption of drugs for systemic use, as it contains a
vast network of blood vessels. Only a few drugs are administered by this route at present,
however. Among these are oestrogens and prostaglandin analogues, which are usually
administered as vaginal creams or hydrogels. Progesterone has been given as vaginal
suppositories (pessaries) for some years, and better results are obtained in this way than after oral
dosing.
Formulation of vaginal dosage forms

Many different types of formulations have been and are applied vaginally, e.g. tablets, capsules,
pessaries, solutions, sprays, foams, creams and ointments. Because of the rather low moisture
content under normal physiological conditions, additives are used to improve the disintegration
of vaginal tablets, e.g. bicarbonate together with an organic acid, which results in CO2 release. A
good filler for vaginal tablets is lactose, as this is a natural substrate for the vaginal microflora,
which converts lactose into lactic acid, resulting in a pH value of 4-4.5. Vaginal suppositories
(pessaries) are mostly prepared with glycerol-gelatin bases, as this mixture is well tolerated.
Polyethylene glycols are less common because they are said to promote irritation. Also, fatty
excipients are not much used. Most delivery forms for vaginal application demand an auxiliary
device to obtain deep insertion of the delivery system.

Chapter Three: POWDERS AND GRANULES
The term 'powder' when used to describe a dosage form describes a formulation in which a drug
powder has been mixed with other powdered excipients to produce the final product. The
function of the added excipients depends upon the intended use of the product. Colouring,
flavouring and sweetening agents, for example, may be added to powders for oral use.
Conventionally, the title 'powder' should be restricted to powder mixes for internal use, and
alternative titles are used for other powdered formulations, e.g. dusting powders, which are for
external use. The more descriptive title 'oral powder' to differentiate powders for internal use is
recommended. Granules which are used as a dosage form consistof powder particles that have
been aggregated to form a larger particle, which is usually 2-4 mm in diameter. This is much
larger than granules prepared as an intermediate for tablet manufacture..
Powdered and granulated products are traditionally dispensed as:
• bulk powders or granules for internal use
• divided powders or granules (i.e. single preparations) for internal use
• dusting powders for external use.
Other preparations which are presented as powders or granules include:
• insufflations for administration to ear, nose or throat
• antibiotic syrups to be reconstituted before use
• powders for reconstitution into injections
• dry powder inhalers.
Advantages and disadvantages of powdered and granulated products
The advantages of this type of preparation are as follows.
1. Solid preparations are more chemically stable than liquid ones. The shelf-life of powders
for antibiotic syrups, for example, is 2-3 years, but once they are reconstituted with water
it is 1-2 weeks. The instability observed in liquid preparations is usually the primary
reason for presenting some injections as powders to be reconstituted just prior to use.
2. Powders and granules are a convenient form in which to dispense drugs with a large dose.
The dose of Compound Magnesium Trisilicate Oral Powder is 1-5 g, and although it is
feasible to manufacture tablets to supply this dose it is often more acceptable to the
patient to disperse a powder in water and swallow it as a draught.
3. Orally administered powders and granules of soluble medicaments have a faster
dissolution rate than tablets or capsules, as these must first disintegrate before the drug
dissolves. Drug absorption from such powdered or granulated preparations will therefore
be faster than from the corresponding tablet or capsule, if the dissolution rate limits the
rate of drug absorption.
The disadvantages of powders and granules are as follows.
1. Bulk powders or granules are far less convenient for the patient to carry than a small
container of tablets or capsules, and are as inconvenient as liquid preparations, such as
mixtures. Modern packaging methods for divided preparations, such as heat-sealable
laminated sachets, mean that individual doses can be conveniently carried.
2. The masking of unpleasant tastes may be a problem with this type of preparation. A
method of attempting this is by formulating the powder into a pleasantly tasting or taste-

masked effervescent product, whereas tablets and capsules are a more common
alternative for low-dose products.
3. Bulk powders or granules are not suitable for administering potent drugs with a low dose.
This is because individual doses are extracted from the bulk using a 5 mL spoon. This
method is subject to such variables as variation in spoon fill (e.g. 'level' or 'heaped'
spoonfuls) and variation in the bulk density of different batches of a powder. It is
therefore not an accurate method of measurement. Divided preparations have been used
for more potent drugs, but tablets and capsules have largely replaced them for this
purpose.
4. Powders and granules are not a suitable method for the administration of drugs which are
inactivated in, or cause damage to, the stomach; these should be presented as enteric-
coated tablets, for example.
PARTICLE SIZE AND ANALYSIS
The particles of pharmaceutical powders and granules may range from being extremely coarse,
about 10 mm (1 cm) in diameter, to extremely fi ne, approaching colloidal dimensions of 1 µm or
less. In order to characterize the particle size of a given powder, the United States Pharmacopeia
(USP) uses these descriptive terms: very coarse, coarse, moderately coarse, fi ne, and very fi ne,
which are related to the proportion of powder that is capable of passing through the openings of
standard sieves of varying fi neness in a specifi ed period while being shaken, generally in a
mechanical sieve shaker (2). Table 6.1 presents the standard sieve numbers and the openings in
each, expressed in millimeters and in microns. Sieves for such pharmaceutical testing and
measurement are generally made of wire cloth woven from brass, bronze, or other suitable wire.
They are not coated or plated.
Powders of vegetable and animal origin drugs are officially defi ned as follows (2):
Very coarse (No. 8): All particles pass through a No. 8 sieve and not more than 20% pass
through a No. 60 sieve.
• Coarse (No. 20): All particles pass through a No. 20 sieve and not more than 40% pass through
a No. 60 sieve.
• Moderately coarse (No. 40): All particles pass through a No. 40 sieve and not more than 40%
pass through a No. 80 sieve.
• Fine (No. 60): All particles pass through aNo. 60 sieve and not more than 40% pass through a
No. 100 sieve.
• Very fi ne (No. 80): All particles pass through a No. 80 sieve. There is no limit to greater fi
neness.
Granules typically fall within the range of 4- to 12-sieve size, although granulations of powders
prepared in the 12- to 20-sieve range are sometimes used in tablet making.
The purpose of particle size analysis in pharmacy is to obtain quantitative data on the size,
distribution, and shapes of the drug and other components to be used in pharmaceutical
formulations. There may be substantial differences in particle size, crystal morphology, and
amorphous character within and between substances. Particle size can infl uence a variety of
important factors, including the following:
• Dissolution rate of particles intended to dissolve; drug micronization can increase the rate
of drug dissolution and its bioavailability
• Suspendability of particles intended to remain undissolved but uniformly dispersed in a
liquid vehicle (e.g., fi ne dispersions have particles approximately 0.5 to 10 µm)
• Uniform distribution of a drug substance in a powder mixture or solid dosage form to
ensure dose-to-dose content uniformity (3)
• Penetrability of particles intended to be inhaled for deposition deep in the respiratory
tract (e.g., 1 to 5 µm) (4)
• Lack of grittiness of solid particles in dermal ointments, creams, and ophthalmic
preparations (e.g., fi ne powders may be 50 to 100 µm in size)
A number of methods exist for the determination of particle size, including the following
(Physical Pharmacy Capsule 6.1):
• Sieving, in which particles are passed by mechanical shaking through a series of sieves of
known and successively the proportion of powder passing through or being withheld on
each sieve is determined (range about 40 to 9,500 mµm, depending upon sieve sizes) (2,
5).
• Microscopy, in which sample particles are sized through the use of a calibrated grid
background or other measuring device (range 0.2 to 100 µm) (6, 7).
• Sedimentation rate, in which particle size is determined by measuring the terminal
settling velocity of particles through a liquid medium in a gravitational or centrifugal
environment (range 0.8 to 300 µm) (5). Sedimentation rate may be calculated from
Stokes’ law.
• Light energy diffraction or light scattering, in which particle size is determined by the
reduction in light reaching the sensor as the particle, dispersed in a liquid or gas, passes
through the sensing zone (range 0.2 to 500 µm) (4). Laser scattering utilizes a He-N laser,
silicon photo diode detectors, and an ultrasonic probe for particle dispersion (range 0.02
to 2,000 µm) (8).
• Laser holography, in which a pulsed laser is fi red through an aerosolized particle spray
and is photographed in three dimensions with a holographic camera, allowing the
particles to be individually imaged and sized (range 1.4 to 100 µm) (9).

• Cascade impaction, which is based on the principle that a particle driven by an airstream
will hit a surface in its path, provided its inertia is suffi cient to overcome the drag force
that tends to keep it in the airstream
• (10). Particles are separated into various size ranges by successively increasing the
velocity of the airstream in which they are carried.
• Online methods for determining particle sizes during production are available (11).
PHYSICAL PHARMACY CAPSULE 6.1

Micromeritics
Micromeritics is the science of small particles; a particle is any unit of matter having defi ned
physical dimensions. It is important to study particles because most drug dosage forms are solids,
solids are not static systems, the physical state of particles can be altered by physical
manipulation, and particle characteristics can alter therapeutic effectiveness. Micromeritics is the
study of a number of characteristics, including particle size and size distribution, shape, angle of
repose, porosity, true volume, bulk volume, apparent density, and bulkiness.
PARTICLE SIZE
A number of techniques can be used to determine particle size and size distributions. Particle size
determinations are complicated by the fact that particles are not uniform in shape. Only two
relatively simple examples are provided for a detailed calculation of the average particle size of a
powder mixture. Other methods are generally discussed. The techniques used include the
microscopic method and the sieving method.
The microscopic method can include not fewer than 200 particles in a single plane using a
calibrated ocular on a microscope. Given the following data, what is the average diameter of the
particles?

The sieving method entails using a set of U.S. standard sieves in the desired size range. A stack
of sieves is arranged in order, the powder placed in the top sieve, the stack shaken, the quantity
of the powder resting on each sieve weighed, and this calculation performed:
Another method of particle size determination entails sedimentation using the Andreasen pipet, a
special cylindrical container from which a sample can be removed from the lower portion at
selected intervals. The powder is dispersed in a nonsolvent in the pipette and agitated, and 20-
mL samples are removed over time. Each 20-mL sample is dried and weighed. The particle
diameters can be calculated from this equation:
Other methods of particle size determinations include elutriation, centrifugation, permeation,

adsorption, electronic sensing zone (the Coulter counter), and light obstruction. The last includes
both standard light and laser methods. In general, the resulting average particle sizes by these
techniques can provide the average particle size by weight (sieve method, light scattering,
sedimentation method), and the average particle size by volume (light scattering, electronic
sensing zone, light obstruction, air permeation, and even the optical microscope).
ANGLE OF REPOSE

The angle of repose is a relatively simple technique for estimating the flow properties of a
powder. It can easily be determined by allowing a powder to fl ow through a funnel and fall
freely onto a surface. The height and diameter of the resulting cone are measured and the angle
of repose is calculated from this equation:
EXAMPLE 1
A powder was poured through the funnel and formed a cone 3.3 cm high and 9 cm in diameter.
What is the angle of repose? tan θ = h/r = 3.3/4.5 = 0.73 arc tan 0.73 = 36.25°
Powders with a low angle of repose flow freely, and powders with a high angle of repose flow
poorly. A number of factors, including shape and size, determine the flow properties of powders.
Spherical particles flow better than needles. Very fi ne particles do not flow as freely as large
particles. In general, particles in the size range of 250 to 2,000 µm flow freely if the shape is
amenable. Particles in the size range of 75 to 250 µm may flow freely or cause problems,
depending on shape and other factors. With most particles smaller than 100 µm, flow is a
problem.
POROSITY, VOID, AND BULK VOLUME

If spheres and the different ways they pack together are used as an example, two possibilities
arise. The closest packing may be rhombus-triangle, in which angles of 60° and 120° are
common. The space between the particles, the void, is about 0.26, resulting in porosity, as
described later, of about 26%. Another packing, cubical, with the cubes packed at 90° angles to
each other, may be considered. This results in a void of about 0.47, or a porosity of about 47%.
This is the most open type of packing. If particles are not uniform, the smaller particles will slip
into the void spaces between the larger particles and decrease the void areas.
Packing and flow are important, as they affect the size of the container required for packaging,
the flow of granulations, the efficiency of the filling apparatus for making tablets and capsules,
and the ease of working with the powders.
The characteristics used to describe powders include porosity, true volume, bulk volume,
apparent density, true density, and bulkiness. The photo is a tapped density tester.

Porosity is Void x 100

This value should be determined experimentally by measuring the volume occupied by a selected
weight of a powder, Vbulk. The true volume, V, of a powder is the space occupied by the
powder exclusive of spaces greater than the intramolecular space.
Void can be defined as

DISPENSED PREPARATIONS
Bulk powders
The mixed ingredients are packed into a suitable bulk container, such as a wide-mouthed glass
jar. Because of the disadvantages of this type of preparation the constituents are usually
relatively non-toxic medicaments with a large dose, e.g. magnesium trisilicate and chalk, as

present in Compound Magnesium Trisilicate Oral Powder. Relatively few proprietary examples
exist, although many dietary/ food supplements are packed in this way.
Divided powders
Divided powders are similar formulations to bulk powders but individual doses are separately
wrapped. Traditionally, single doses were wrapped in paper. This was unsatisfactory for most
products, particularly if the ingredients were hygroscopic, volatile or deliquescent. Modern
packaging materials of foil and plastic laminates have replaced such paper wrappings because
they offer superior protective qualities and are amenable to use on high-speed packing machines.
Effervescent powders can now be packed in individual dose units because of the protective
qualities of laminates. Such powders contain, for example, sodium bicarbonate and citric acid,
which react and effervesce when the patient adds the powder to water to produce a draught. It is
important to protect the powder from the ingress of moisture during manufacture and on
subsequent storage to prevent the reaction occurring prematurely.
All powders and granules should be stored in a dry place to prevent deterioration due to ingress
of moisture. Even if hydrolytic decomposition of susceptible ingredients does not occur, the
particles will adhere and cake, producing an inelegant, often unusable product.
Bulk granules
One disadvantage of bulk powders is that, because of particle size differences, the ingredients
may segregate (see Chapter 13), either on storage in the final container or in the hoppers of
packaging machines. If this happens the product will be non-uniform and the patient will not
receive the same dose of the ingredients on each occasion. This can be prevented by granulating
the mixed powders.
Bulk granules therefore contain similar medicaments to powders, i.e. those with low-toxicity,
highdose drugs. Methylcellulose Granules, for example, are used as a bulk-forming laxative and
have a dose of 1-4 g daily. Many proprietary preparations contain similar bulk-forming laxatives.
Divided granules
These are granulated products in which sufficient for one dose is individually wrapped.
Effervescent granules can be formulated and presented in this manner. The comments on
packaging materials discussed under Divided powders above are also equally pertinent to divided
granules.
Dusting powders
Dusting powders contain ingredients used for therapeutic, prophylactic or lubricant purposes and
are intended for external use. Only sterile dusting powders should be applied to open wounds.
Such preparations should be prepared using materials and methods designed to ensure sterility
and to avoid the introduction of contaminants and the growth of microorganisms.
Dusting powders for lubricant purposes or superficial skin conditions need not be sterile but they
should be free from pathogenic organisms. As minerals such as talc and kaolin may be
contaminated at source with spores of organisms causing tetanus and gangrene, these should be
sterilized before they are incorporated into the product. Talc dusting powder is a sterile

cutaneous powder containing starch and purified talc in which the talc is sterilized before
incorporation with the starch, or the final product is subject to a suitable terminal sterilization
procedure.
Dusting powders are normally dispensed in glass or metal containers with a perforated lid. The
powder must flow well from such a container, so that they can be dusted over the affected area.
The active ingredients must therefore be diluted with materials having reasonably good flow
properties, e.g. purified talc or maize starch.
Hexachlorophane Dusting Powder contains an antibacterial agent and Talc Dusting Powder is
used as a lubricant to prevent chafing. Proprietaryproducts are available, usually for the
treatment of bacterial or fungal infections, e.g. Canesten Powder (clotrimazole) is used as an
antifungal agent and CX Powder (containing chlorhexidine acetate) is used as a general skin
disinfectant.
GRANULES
As indicated previously, granules are prepared agglomerates of smaller particles of powder.
They are irregularly shaped but may be prepared to be spherical. They are usually in the 4- to 12-
mesh sieve size range, although granules of various mesh sizes may be prepared depending upon
their application.
Granules are prepared by wet methods and dry methods. One basic wet method is to moisten the
powder or powder mixture and then pass the resulting paste through a screen of the mesh size to
produce the desired size of granules. The granules are placed on drying trays and are dried by air
or under heat. The granules are periodically moved about on the drying trays to prevent adhesion
into a large mass. Another type of wet method is fl uid bed processing, in which particles are
placed in a conical piece of equipment and are vigorously dispersed and suspended while a liquid
excipient is sprayed on the particles and the product dried, forming granules or pellets of defi ned
particle size (Fig. 6.10).
The dry granulation method may be performed in a couple of ways. By one method, the dry
powder is passed through a roll compactor enclose individual doses or units of use rather than
folding individual powder papers. These envelopes are usually moisture resistant, and their use
results in uniform packaging. Today, powder papers are rarely used on an out-patient,
community practice basis and their use is confined to institutional and research practice.
EFFERVESCENT GRANULATED SALTS

Effervescent salts are granules or coarse to very coarse powders containing a medicinal agent in
a dry mixture usually composed of sodium bicarbonate, citric acid, and tartaric acid. When added
to water, the acids and the base react to liberate carbon dioxide, resulting in effervescence. The
resulting carbonated solution masks undesirable taste of any medicinal agent. Using granules or
coarse particles of the mixed powders rather than small powder particles decreases the rate of

solution and prevents violent and uncontrollable effervescence. Sudden and rapid effervescence
could overfl ow the glass and leave little residual carbonation in the solution.
Using a combination of citric and tartaric acids rather than either acid alone avoids certain
difficulties. When tartaric acid is used as the sole acid, the resulting granules readily lose their
firmness and crumble. Citric acid alone results in a sticky mixture difficult to granulate.


Chapter Four: Diffusion and Dissolution

THE PROCESS OF DISSOLUTION
States of matter
The kinetic theory of matter indicates that in condensed phases the thermal motions of molecules
are reduced sufficiently so that intermolecular forces of attraction result in the formation of
coherent masses of molecules, unlike the situation in gaseous phases, where the molecules move
independently within the confines of the container. In solid condensed phases the thermal motion
of molecules (or ions) is virtually restricted to vibrations about mean positions and the
components tend to form three-dimensional arrangements or crystal lattices in which the
intercomponent forces are best satisfied and the potential energy of the system is minimized.
In liquid condensed systems the thermal motions of molecules are greater than those in solids but
less than those in gases. The structure of liquids is therefore intermediate between that of solids
and that of gases. Thus, although the molecules can move within the confines of the liquid phase
boundaries small groups of them tend to form regular arrangements in a transient manner. In
addition, liquids are thought to contain a small amount of so-called 'free volume' in the form of
'holes' which, at a given instant, are not occupied by the solvent molecules themselves When a
substance dissolves in a liquid the increase in volume of the latter is less than would be expected.
The process of dissolution may therefore be considered to involve the relocation of a solute
molecule from an environment where it is surrounded by other identical molecules, with which it
forms intermolecular attractions, into a cavity in a liquid, where it is surrounded by non-identical
molecules, with which it may interact to different degrees.
DISSOLUTION RATES OF SOLIDS IN LIQUIDS
Dissolution mechanisms
The dissolution of a solid in a liquid may be regarded as being composed of two consecutive
stages.
1. First is an interfacial reaction that results in the liberation of solute molecules from the
solid phase. This involves a phase change, so that molecules of solid become molecules
of solute inthe solvent in which the crystal is dissolving. The solution in contact with the
solid will be saturated (because it is in direct contact with undissolved solid). Its
concentration will be Cs, a saturated solution.
2. After this, the solute molecules must migrate through the boundary layers surrounding
the crystal to the bulk of the solution, at which time its concentration will be C. This step
involves the transport of these molecules away from the solid-liquid interface into the
bulk of the liquid phase under the influence of diffusion or convection. Boundary layers
are static or slow moving layers of liquid that surround all wetted solid surfaces.
Mass transfer takes place more slowly through these static or slow-moving layers, which inhibit
the movement of solute molecules from the surface of the solid to the bulk of the solution. The
concentration of the solution in the boundary layers changes therefore from being saturated (Cs)
at the crystal surface to being equal to that of the bulk of the solution (C) at its outermost limit.
These stages are illustrated in Figure 2.1.

Like any reaction that involves consecutive stages, the overall rate of dissolution will depend on
whichever of these steps is the slowest (the rate determining or rate-limiting step). In dissolution
the interfacial step ((1) above) is virtually instantaneous and so the rate of dissolution will be
determined by the rate of the slower step ((2) above), of diffusion of dissolved solute across the
static boundary layer of liquid that exists at a solid-liquid interface.
The rate of diffusion will obey Pick's law of diffusion, i.e. the rate of change in concentration of
dissolved material with time is directly proportional to the concentration difference between the
two sides of the diffusion layer, i.e.,
Where, the constant k is the rate constant (s-1).
In the present context AC is the difference in concentration of solution at the solid surface (C\)
and Fig. 2.1 Diagram of boundary layers and concentration change surrounding a dissolving
particle. the bulk of the solution (C2). At equilibrium, the solution in contact with the solid (C1)
will be saturated (concentration = Cs), as discussed above.

If the concentration of the bulk (C2) is greater than this, the solution is referred to as
supersaturated and the movement of solid molecules will be in the direction of bulk to surface (as
during crystallization), and if C2 is less than saturated the molecules will move from the solid to
the bulk (as during dissolution).
An equation known as the Noyes-Whitney equation was developed to define the dissolution from
a single spherical particle. The rate of mass transfer of solute molecules or ions through a static
diffusion layer (dm/dt) is directly proportional to the area available for molecular or ionic
migration (A), the concentration difference (AC) across the boundary layer, and is inversely
proportional to the thickness of the boundary layer (h). This relationship is shown in Eqn 2.6, or
in a modified form in Eqn 2.7.
Where, the constant k1 is known as the diffusion coefficient, D, and has the units of m2/s.
If the solute is removed from the dissolution medium by some process at a faster rate than it
passes into solution, then the term (Cs - C) in Eqn 2.7 may be approximated to Cs. Alternatively,
if the volume of the dissolution medium is so large that C is not allowed to exceed 10% of the
value of Cs, then the same approximation may be made in particular.
In either of these circumstances dissolution is said to occur under 'sink' conditions, and Eqn 2.7
may be simplified to
It should be realized that such 'sink' conditions may arise in vivo when a drug is absorbed from
its solution in the gastrointestinal fluids at a faster rate than it dissolves in those fluids from a
solid dosage form such as a tablet. If solute is allowed to accumulate in the dissolution medium
to such an extent that the above approximation is no longer valid, i.e. when C > Cs/10, then 'non-
sink' conditions are said to be in operation. When C = Cs it is obvious from Eqn 2.7 that the
overall dissolution rate will be zero, as the dissolution medium is saturated with solute.
Summary of factors affecting dissolution rates

These factors may be derived from a consideration of the terms that appear in the Noyes-
Whitney equation (Eqn 2.7) and a knowledge of the factors that in turn affect these terms. Most
of the effects of these factors are included in the summary given in Table 2.1. It should be borne

in mind that pharmacists are often concerned with the rate of dissolution of a drug from a
formulated product such as a tablet or a capsule, as well as with the dissolution rates of pure
solids. Later chapters in this book should be consulted for information on the influence of
formulation factors on the rates of release of drugs into solution from various dosage forms.
Intrinsic dissolution rate

Because the rate of dissolution is dependent on so many factors, it is advantageous to have a

measure of the rate of dissolution which is independent of rate of agitation, area of solute
available etc. In the latter case this will change greatly in a conventional tablet formulation, as
the tablet breaks up into granules and then into primary powder particles as it comes into contact
with water.
This is known as the intrinsic dissolution rate (IDR), which is the rate of mass transfer per area of dissolving surface
and typically has the units of mg crrr2 mirr1. IDR should be independent of boundary layer thickness and volume of
solvent (if sink conditions are assumed).Thus:
Thus IDR measures the intrinsic properties of the drug only as a function of the dissolution medium, e.g. its pH,
ionic strength, counter ions etc).



COLLIGATIVE PROPERTIES
When a non-volatile solute is dissolved in a solvent certain properties of the resultant solution
are largely independent of the nature of the solute and are determined by the concentration of
solute particles. These properties are known as colligative properties. In the case of a non-
electrolyte the solute particles will be molecules, but if the solute is an electrolyte then its degree
of dissociation will determine whether the particles will be ions only or a mixture of ions and
undissociated molecules.
The most important colligative property from a pharmaceutical point of view is referred to as
osmotic pressure. However, as all colligative properties are related to each other by virtue of
their common dependency on the concentration of the solute molecules, the remaining
colligative properties (which are lowering of vapour pressure of the solvent, elevation of its
boiling point and depression of its freezing point) are of pharmaceutical interest. These other
observations offer alternative means to osmotic pressure determinations as methods of
comparing the colligative properties of different solutions.
Osmotic pressure
The osmotic pressure of a solution is the external pressure that must be applied to the solution in
order to prevent it being diluted by the entry of solvent via a process known as osmosis. This
refers to the spontaneous diffusion of solvent from a solution of low solute concentration (or a
pure solvent) into a more concentrated one through a semipermeable membrane. Such a
membrane separates the two solutions and is permeable only to solvent molecules. Because the
process occurs spontaneously at constant temperature and pressure, the laws of thermodynamics
indicate that it will be accompanied by a decrease in the so-called free energy (G) of the system.
This free energy may be regarded as the energy available in the system for the performance of
useful work, and when an equilibrium position is attained then there is no difference between the
states that are in equilibrium. The rate of increase in free energy of a solution caused by an
increase in the number of moles of one component is termed the partial molar free energy (G) or
chemical potential (/x) of that component. For example, the chemical potential of the solvent in a
binary solution is given by:
Where, the subscripts outside the bracket on the left hand side indicate that temperature, pressure
and amount of component 1 (the solute in this case) remain constant. Because only solvent can
pass across the semipermeable membrane, the driving force for osmosis arises from the
inequality of the chemical potentials of the solvent on opposing sides of the membrane. Thus the
direction of osmotic flow is from the dilute solution (or pure solvent), where the chemical
potential of the solvent is highest because there are more moles of it, into the concentrated
solution, where the number of moles and, consequently, the chemical potential of the solvent is
reduced by the presence of more solute. The chemical potential of the solvent in the more

concentrated solution can be increased by forcing its molecules closer together under the
influence of an externally applied pressure.
Osmosis can therefore be prevented by such means, hence the definition of osmotic pressure.
The relationship between osmotic pressure (TT) and the concentration of a non-electrolyte is
given for dilute solutions, which may be assumed to exhibit ideal behaviour, by the van't Hoff
equation:
Where, V is the volume of solution, n2 is the number of moles of solute, T is the thermodynamic
temperature and R is the gas constant. This equation, which is similar to the ideal gas equation,
was derived empirically but it does correspond to a theoretically derived equation if
approximations based on low solute concentrations are taken into account. If the solute is an
electrolyte, Eqn 3.19 must be modified to allow for the effect of ionic dissociation, because this
will increase the number of particles in the solution. This modification is achieved by insertion of
the van't Hoff correction factor (i) to give:
Osmolality and osmolarity

The amount of osmotically active particles in a solution is sometimes expressed in terms of
osmoles or milliosmoles (1 osmol = 1 x 103 mosmol). These may be either molecules or ions.
The concentration of a solution may therefore be expressed in terms of its osmolality or its
osmolarity, where osmolality is the number of osmoles per kilogram of water and osmolarity is
the number of osmoles per litre of solution.
Iso-osmotic solutions
If two solutions are separated by a perfect semipermeable membrane, i.e. a membrane which is
permeable only to solvent molecules, and no net movement of solvent occurs across the
membrane, then the solutions are said to be iso-osmotic and will have equal osmotic pressures.
Isotonic solutions
Biological membranes do not always function as perfect semipermeable membranes and some
solute molecules as well as water are able to pass through them. If two iso-osmotic solutions
remain in osmotic equilibrium when separated by a biological membrane they may be described
as being isotonic with respect to that particular membrane. Adjustment of isotonicity is

particularly important for formulations intended for parenteral routes of administration.

DIFFUSION IN SOLUTION
By definition, the components of a solution form a single phase, which is homogeneous. This
homogeneity arises from the process of diffusion, which occurs spontaneously and is
consequently accompanied by a decrease in the free energy (G) of the system. Diffusion may be
defined as the spontaneous transference of a component from a region in the system where it has
a high chemical potential into one where its chemical potential is lower.
Although such a gradient in chemical potential provides the driving force for diffusion, the laws
that describe this phenomenon are usually expressed in terms of concentration gradients, for
example Pick's first law. The most common explanation of the mechani

Chapter Five: Kinetics and drug stability

Introduction
Kinetics is the study of the rate at which processes occur. The changes may be chemical
(decomposition of a drug, radiochemical decay) or physical (transfer across a boundary, such as
the intestinal lining or skin). Kinetic studies are useful in providing information that:
1. gives an insight into the mechanisms of the changes involved, and
2. Allows a prediction of the degree of change that will occur after a given time has elapsed.
In general, the theories and laws of chemical kinetics are well founded and provide a sound basis
for the application of such studies to pharmaceutical problems that involve chemical reactions,
e.g. the decomposition of medical compounds.
Order
This is the number of concentration terms that determine the rate. In an unimolecular process a
molecule will react if it has sufficiently high-energy.The number of high-energy molecules
depends on how many molecules are present, i.e. their concentration in solution (or pressure in a
gas). In a bimolecular process two molecules must collide to react, and the likelihood of collision
depends on the concentrations of each species. The law of mass action states that the rate
depends on the product of concentrations of the reactants.
Thus in the first step of the example reaction,
The rate of reaction = k\ [N2O5], i.e. there is only one concentration term and the reaction is
known as first order.
In the second step,
the rate of reaction = , where kl and k2 are the reaction rate

constants. Thus there are two concentration terms and the reaction is known as second order.
Each of these is discussed in more detail below.
First order
The rate is determined by one concentration term. These are by far the most important processes
in pharmaceutical science. Many drug decompositions on storage and the passage of drugs from
one body compartment to another, e.g. lumen of the intestine into blood, follow first-order
kinetics. The rate of reaction is most simply defined as the concentration change divided by the
corresponding time change:

The negative sign is used because concentration falls as time increases. This makes the rate
constant, k,
The differential equation above describes infinitely small changes. For real changes these small
changes are summed (integrated), usually from the start of the process (time = 0, concentration =
c0) to the concentration, c, remaining at any other time, t.
Thus a plot of In c against t is a straight line with intercept c0 and gradient -k.
The units of k are given by rearranging Eqn 7.1:
i.e. the rate constant has the dimensions of time-1 and typical units of s-1. Note that because k
contains no concentration term it is not necessary to convert experimental data to concentration
values in order to estimate it. Any convenient property of the system that is directly proportional
to concentration can be used, such as UV absorbance, conductivity, pressure or radioactivity.
For example, absorbance (A) is related to concentration, c, by Beer's law, i.e. c = aA, where a is a
proportionality constant. Substitution into Eqn 7.2 gives: In aA — In aA0 – kt hence \nA = ]n.A0-
kt. Thus, although the intercept of the graph will alter, the gradient remains the same.
Example 7.1
Consider the following. A tritiated cardiac stimulant is administered by i.v. injection. Blood
samples have the following radioactivity counts per second (cps):

Consider the hydrolysis of ethyl acetate:
Strictly the reaction is second order and the rate of reaction is expressed as:
However, in a dilute aqueous solution of ethyl acetate, [H2O] is very large compared to
[CH3COOEt] and hardly alters during the course of the reaction. [H2O] can be taken as a
constant and incorporated into the second-order rate constant, k':
where k'= k[H2O].
Thus the reaction is, in effect, first order with a rate constant k'. This applies to many drug
decompositions by hydrolysis in aqueous solution.
Second order
Rate depends on the product of two concentration terms. In the simplest case they refer to the
same species. For example:
Here the reaction is not simply a matter of an HI molecule falling apart, but relies on the
collision of two HI molecules. The rate of reaction from the law of mass action is given by:

If the reaction is between two different species, A and B, it is unlikely that their starting
concentrations will be equal. Let their initial concentrations be a0 and b0 (where a0 > b0),
falling to a and b at time t. As equal numbers of molecules of A and B are lost in the
decomposition, the rate can be defined as da/dt
(or db/dt).Thus:

Zero order
In a zero-order reaction the rate of reaction (decomposition, dissolution, drug release) is
independent of the concentration of the reactants, i.e. the rate is constant. A constant rate of drug
release from a dosage form is highly desirable. Zero-order kinetics often apply to processes
occurring at phase boundaries, where the concentration at the surface remains constant either
because reaction sites are saturated (enzyme kinetics, drug receptor interaction) or are constantly
replenished by diffusion of fresh material from within the bulk of one phase. This diffusion
criterion applies to the hydrolysis of drugs in suspensions or delivery from controlled-release
dosage forms such as transdermal patches.

Thus, a plot of c against t is a straight line with gradient k. Units of k from Eqn 7.5 are cone
time"1, with typical units of mole L"1 s^1 or similar.
Example 7.3
Note: strictly speaking, 'amount' is not the same as 'concentration'. In this case concentration is
µg Patch-1.
Half-life (fi)
This is the time taken for the concentration (of, say, a drug in solution) to reduce by a half.
Rearrangement of the integrated equations for t (Eqns 7.2, 7.4 and
7.6) gives:

Note that for first-order reactions the half life, tl3 is independent of concentration.
Table 7.1 summarizes the parameters for zero order, first-order and second-order processes.
Determination of order and rate constant from experimental data

This can achieved in two ways:
1. Substituting the data into the integrated equations and observing which plot is a straight
line;
2. Finding t1\2 values at different stages of thereaction and noting whether and how they
vary with 'starting' concentration.


Data plotting method

The data are plotted in Figure 7.4. The plot of c against t (Fig. 7.4(a)) is obviously not linear and
so the reaction is not zero order. A plot of lie against time (Fig. 7.4(b)) is not linear, so the
reaction is not second order.
The plot of In c against t (Fig. 7.4(c)) is linear and so the reaction is first order. From the graph,
the gradient (i.e. -k) is -0.048 h"1 and the first-order rate constant is 0.048 tr1.
Half-life method
This involves the selection of a set of convenient 'initial' concentrations and then determining the
times taken to fall to half these values.
Within experimental error t\ seems independent of 'c0'3 suggesting that the reaction is first order.
To confirm this it is necessary to check whether t\ values correspond to zero- or to second-order
kinetics. If the reaction were zero order, then cJ2ti would be a constant value (K). Similarly, for a
second-order reaction k = \lc0t\ would be constant. Calculating these gives:
Thus neither set of values is constant, confirming that the reaction is neither zero or second
order.

The first-order rate constant is found from the mean ti value of 13 h, i.e. k = 0.693/fi = 0.053 Ir1.
Effect of temperature on reaction rate

Generally, increasing temperature increases the rate of reaction, and an often-quoted rough guide
is that a 10°C rise doubles the rate constant. Better descriptions are given by the Arrhenius
theory and the more rigorous transition state theory (see, for example, Martin 1993).
Arrhenius theory
This can be developed from simple basic ideas and leads to an equation that is formally identical
with the transition state theory. Consider the simple bimolecular reaction:
The original proposition was that if two molecules collided they would react. The collision
number, Z, can be calculated from the kinetic theory of gases, and it was found that the number
of molecules reacting per second, µ, was much smaller than Z. The theory was modified to
propose that the colliding molecules must have sufficient energy to form an unstable
intermediate, which breaks down to form the product.
The fraction of molecules with at least this activation energy, E, was calculated by Boltzmann as
so that µ= . This equation adequately describes simple reactions such as the
decomposition of HI, but for even slightly more complex reactions, such as:
µ is thousands of times smaller than . This is because the nitrogen atom is shielded by a
mass of C and H atoms, so that only very few collisions occur between the nitrogen and the
carbon of the approaching CH3I.Thus an orientation factor, P, often with a very small value,
must also be included:
The rate constant k is proportional to µ. So, writing k as aµgives:
Over a small temperature range the change in Z with T is negligible compared to that in the
term, so that aPZ is a constant, A. A is called the 'frequency factor', as it is related to the
frequency of correctly aligned collisions.

This is the Arrhenius equation, and may also be written as:
so that a plot of In k (or log k} against (1/7) is a straight line, enabling the calculation of E and A
from the gradient and intercept (remember that T must be in K, not °C).The same equation holds
for zero- and first-order reactions. Here the molecule Iog10 form: will react if it has energy > E.
The collision and orientation factors are inapplicable and A is now the proportionality constant a,
although it is still termed the frequency factor.
ACCELERATED STABILITY TESTING

All medicinal products decompose with time. Paradoxically, when this decomposition is being
assessed the skilled formulator becomes a victim of his own expertise, as a good formulation will
take a long time to decompose. Instabilities in modern formulations are often detectable only
after considerable storage periods under normal conditions. To assess the stability of a
formulated product it is usual to expose it to 'high stress', i.e. conditions of temperature, humidity
and light intensity that are known from experience to be likely causes of breakdown.
High stress conditions enhance the deterioration of the product and therefore reduce the time
required for testing. This enables more data to be gathered in a shorter time, which in turn will
allow unsatisfactory formulations to be eliminated early in a study and will also reduce the time
for a successful product to reach the market. It must be emphasized that extrapolations to
'normal' storage conditions must be made with care, and that the formulator must be sure that
such extrapolations are valid. It is advisable therefore to run concurrently a batch under expected
normal conditions to confirm later that these assumptions are valid.
The objectives of such accelerated tests may be defined as:

1. The rapid detection of deterioration in different initial formulations of the same product. This
is of use in selecting the best formulation from a series of possible choices;
2. The prediction of shelf-life, which is the time a product will remain satisfactory when stored
under expected or directed storage conditions;
3. The provision of a rapid means of quality control, which ensures that no unexpected change
has occurred in the stored product.
Good formulations will invariably break down more slowly than poor ones. Even though no
absolute conclusions can be drawn about their predicted stability under normal storage from data

obtained under stress conditions, such tests allow formulations to be optimized relatively
quickly. When the perceived optimal formulation is decided, attempts can be made to predict its
likely stability at proposed storage conditions. These may be at 25°C for ambient room
temperature (or 30°C for use in hot climates), or 0-4°C for a refrigerator.
The amount of decomposition that is acceptable in fixing an expiry date depends on the
particular drug. This will be small if the therapeutic index (ratio of toxic dose/effective dose) is
low, e.g. digoxin, or if the decomposition products are toxic. It might be decided to fix the shelf-
life as being the time taken for 10% of the drug to decompose at 25°C.
Stability testing protocols

Accelerated stability testing requires the careful design of protocols which must define clearly
the following:
1. The temperature and humidity for storage
2. Storage time before sampling
3. The number of batches to be sampled
4. The number of replicates within each batch
5. A suitable light challenge
6. Details of assay.
Although all pharmaceutical products have to satisfy government regulatory authorities,
surprisingly there are no nationally or internationally standardized storage conditions. Storage
conditions during stability testing vary from company to company and even within a single
company. Often different types of products are given different challenges. Two alternative
stability protocol strategies are discussed below.
Factorial analysis
Factorial analysis is a simple approach for gauging the likely effect of additional factors for
which no simple descriptive relationship such as the Arrhenius equation exists. For example, it
may reasonably be suspected that light and humidity cause the degradation of a freeze-dried
antibiotic powder. The powder is therefore stored under low and high stresses in sealed vessels
over water or desiccant on windowsills and in cupboards. After a suitable time the amount of
decomposition is measured and typical results are:
hi = 8%; HI = 39%; hL = 16%; HL = 47%.
(where, for example, hL = low humidity, high light

intensity).
Average decomposition at high humidity,
H = (39 +47)/2 = 42%
Average decomposition at low humidity, h = 12% Thus the scaled effect of humidity is (42 - 12)
= 30%.
Similarly, the effect of light is 8%.
Thus although both light and humidity cause decomposition, humidity poses the greater threat to
stability.
Prediction of shelf-life from accelerated stability testing data

The mathematical prediction of shelf-life is based on the application of the Arrhenius equation,
Eqn 7.12, which indicates the effect of temperature on the rate constant, k, of a chemical
reaction. Figure 7.8 shows that a graph of In k versus the reciprocal of thermodynamic
temperature, l/T, is a straight line. If the slope of this line is determined from the results of
accelerated tests at high temperatures it is possible to determine the value of the rate constant at
other temperatures (e.g. normal room temperature) by extrapolation. Substitution of this value of
k into the appropriate order of reaction (i.e. the rate equation that applies to the reaction involved
in the particular decomposition) allows the amount of decomposition after a given time to be
calculated. As pointed out, this approach involves a knowledge of the order of the reaction
involved, and preliminary experiments are therefore necessary to determine this order.
Several difficulties and limitations are involved in this aspect of accelerated stability testing.
First, as in all accelerated tests, there is the possibility that the application of high stresses may
cause reactions that would not take place under the lower stresses associated with normal storage
conditions. Secondly, the uncertainty surrounding the term 'normal storage conditions' introduces
a difficulty when attempting to forecast the shelf-life of a product. Unless the storage conditions
are defined precisely on the container, allowance should be made for variations in the conditions
likely to be encountered under normal storage.
Attempts to allow for such a contingency often involve accepting the shortest shelf-life for the
range of conditions likely to be encountered. The climate of the country in which a product is to
be marketed is particularly important in defining this range.
Decompositions in formulated products often proceed via a complex reaction series and may
involve simultaneous, consecutive or chain reactions, because the formulated products
themselves are complex systems. In addition, the order of a reaction may change after a certain
time. Predictions of the extent of decomposition at future times are then impracticable, and
prolonged tests under normal storage conditions must be carried out.
In spite of these difficulties the application of accelerated testing to pharmaceutical products is

often useful, and predicted shelf-lives are sufficiently accurate. Statistical methods of designing
such tests have therefore been reported which allow the selection of the number of replicates,
sampling times and other factors involved in the tests to be made on a logical basis to attain the
required degree of accuracy without wasting time on unnecessary experimentation.
Common high stresses or challenges

Temperature challenge
An increase in temperature causes an increase in the rate of chemical reactions. The products are
therefore stored at temperatures higher than room temperature. The nature of the product often
determines the range covered in the accelerated test. Samples are removed at various time
intervals and the extent of decomposition is determined by analysis.
Sensitive analytical methods should be used in all stability tests of this nature, as small changes
may be detected after very short storage periods. The effects caused by high temperatures should
not be confused with those that arise from the effect of low humidity. Such confusion is possible
because the relative humidity inside a high-temperature storage cabinet will be lower than that in

the room. This low humidity causes loss of moisture, which may lead to apparent increases in the
concentration of ingredients. If these concentration changes are not allowed for in subsequent
analyses decomposition may be unsuspected.
The most useful feature of the Arrhenius equation in pharmacy is that it allows the prediction of
reaction rates at proposed storage temperatures from data at high temperatures. Preparations are
stored at high temperatures, thus saving time in developmental formulation studies. However,
extrapolation of results is always a risky business, even from a purely statistical standpoint, when
it is assumed that the plot remains linear over the extrapolated range. Added to this is the (small)
variation in A with temperature and the possibility of change in reaction mechanism with
temperature, i.e. variation in E.

A scheme for continually increasing the storage temperature is sometimes employed. Curvature
of the final plot indicates a change in reaction mechanism, and data collected at low temperatures
are used in the assessment, thereby reducing extrapolation errors.
The Arrhenius equation involves only one rate constant and therefore applies to a simple (single
step) decomposition mechanism. It cannot be used for complex reactions (consecutive, parallel
etc.) or heterogeneous processes involving phase boundaries. Here additional factors, such as

rate of dissolution, diffusion from within a matrix, and melting, are important determinants of
decomposition. All sorts of confounding factors may invalidate the procedure.
For example, the higher temperatures may reduce the moisture content of the product, thus
slowing hydrolysis, gelatin may soften or melt, tablet coatings may split; the effects of
temperature on photochemical and microbiological destruction are unpredictable.
Humidity challenge
Storage of the product in atmospheres of high humidity will accelerate decompositions that result
from hydrolysis. Marked acceleration will be obtained if the 'naked' product (i.e. not enclosed in
a container) is subjected to these tests, which usually indicate the minimum humidity tolerated
by the product without undue decomposition, and are therefore useful in determining the degree
of protection that should be afforded by a container.
Light challenge
A source of artificial light is used to accelerate the effects of sunlight or sky light. The source
should emit a similar distribution of radiant energy to that in sunlight because photochemical
reactions involve the absorption of light of definite wavelengths. Daylight fluorescent lamps
provide a satisfactory source, and banks of such lamps may be used to accelerate the effects of
light. However, although these lamps do not have a marked heating effect the use of glass plates
to reduce such an effect is recommended, otherwise it is difficult to separate the accelerated
decomposition caused by light from that caused by increased temperatures.
Concluding comments
Even if the Arrhenius equation can be applied successfully to predict the effect of temperature,
and the effect of other factors, such as the influence of light and humidity can now be predicted
with some certainty, other factors beyond the control of the formulator must be foreseen. The
end user may store bottles lying down, so that reaction with materials in the cap may occur; if the
preparation is to be used as bulk stock, e.g. 2 L of a cough mixture, it may well be left half-filled
with air after opening for a prolonged period and oxidation may occur; stock containers of tablets
will be continually opened and resealed, admitting moisture from the atmosphere.
It must be remembered that although accelerated storage testing is a useful tool for formulation
studies, the results can only be a guide and may not apply to actual usage. It is essential that final
formulations in their final packaging be stored under conditions that will be encountered in
practice, to provide acceptable data for the licensing authorities.
Summary
Drug and Drug Product Stability: Kinetics and Shelf Life
Stability is the extent to which a product retains within specified limits and throughout its period of storage and use
(i.e., its shelf life) the same properties and characteristics that it possessed at the time of its manufacture.
Five types of stability concern pharmacists:

1. Chemical: Each active ingredient retains its chemical integrity and labeled potency within the specified
limits.
2. Physical: The original physical properties, including appearance, palatability, uniformity, dissolution, and
suspendability are retained.

3. Microbiologic: Sterility or resistance to microbial growth is retained according to the specified
requirements. Antimicrobial agents retain effectiveness within specifi ed limits.
4. Therapeutic: The therapeutic effect remains unchanged.
5. Toxicologic: No signifi cant increase in toxicity occurs.
Chemical stability is important for selecting storage conditions (temperature, light, humidity), selecting the proper
container for dispensing (glass vs. plastic, clear vs. amber or opaque, cap liners), and anticipating interactions when
mixing drugs and dosage forms. Stability and expiration dating are based on reaction kinetics, that is, the study of
the rate of chemical change and the way this rate is influenced by concentration of reactants, products, and other
chemical species and by factors such as solvent, pressure, and temperature. In considering chemical stability of a
pharmaceutical, one must know the reaction order and reaction rate.
Rate Reactions
The reaction rate is a description of the drug concentration with respect to time. Most commonly zero-order and
first-order reactions are encountered in pharmacy. These are presented in Physical Pharmacy Capsule 4.11, Rate
Reactions, along with some appropriate examples.
Q10 Method of Shelf Life Estimation

The Q10 method of shelf life estimation lets the pharmacist estimate shelf life for a product that has been stored or is
going to be stored under a different set of conditions.




Chapter Six: RADIOPHARMACEUTICALS

Introduction
By definition, a radiopharmaceutical is a radioactive pharmaceutical agent that is used for diagnostic or therapeutic
procedures (1). Over the past four decades, the discipline of nuclear pharmacy, or radiopharmacy, has become
highly specialized and contributed positively to the practice of nuclear medicine. Nuclear pharmacy, the first
specialty in pharmacy recognized (in 1978) by the Board of Pharmaceutical Specialties (USA), focuses on the safe
and effective use of radioactive drugs or radiopharmaceuticals.
The application of radiopharmaceuticals is divided into two major areas, diagnostic and therapeutic. The diagnostic
side is well established, while the therapeutic side of nuclear medicine is evolving. For example, more than 100
radiopharmaceutical products are available, with the largest proportion of these having application in cardiology
(e.g., myocardial perfusion), oncology (e.g., tumor imaging and localization), and neurology (e.g., cerebral
perfusion). Diagnostically, they are also used for infection imaging and in nephrology. Historically, nuclear
medicine has been well established as a therapeutic modality for thyroid cancer, Graves disease, hyperthyroidism,
131 123
and bone pain palliation associated with skeletal metastasis. However, recent radiopharmaceuticals (e.g., I or I
labeled MIBG [m-iodobenzylguanidine]) are being used to treat pheochromocytoma and neuroblastoma, and
radiolabeled somatostatin analogues are used for the treatment of neuroendocrine tumors (e.g., neuroblastoma) (2).
Ongoing investigative studies involving radiopharmaceuticals are being conducted for numerous other diseases (e.g.,
primary bone cancers, ovarian cancer) using innovative means (e.g., targeting agents) to deliver the drug to the
tumor. It is anticipated that many of these radiopharmaceuticals will become available for amelioration of diseases.
A radiopharmaceutical consists of a drug component and a radioactive component. Most radionuclides contain a
component that emits gamma radiation. Substances that have varying numbers of protons and neutrons as compared
to stable elements are called radionuclides. Nuclides may be stable or unstable; those that are unstable are
radioactive because their nuclei undergo rearrangement while changing to a stable state, and energy is released.
An important distinction between radiopharmaceuticals and traditional drugs is lack of pharmacologic activity on
the part of radiopharmaceuticals. For intensive purposes, radiopharmaceuticals have been used as tracers of
physiologic processes.
Their huge advantage is that their radioactivity allows noninvasive external monitoring or targeted therapeutic
irradiation with very little effect on the biologic processes in the body. Indeed, radiopharmaceuticals have an
excellent safety record, and their incidence of adverse effects is extremely low (3). However, in the past two decades
there has been committed interest to developing unsealed radionuclides for treatment of cancers arising from the
diversity of newer molecular carriers (e.g., immune-derived molecules, receptor-avid tracers). Technologic advances
in molecular pharmacology, combinatorial chemistry, and peptide biochemistry are providing innovative means
(e.g., targeting vectors) to enhance radionuclide specificity and targeting cancerous cells in vivo.
Systemic administration of radiopharmaceuticals for site-specific use allows the physician to treat widely
disseminated diseases. Optimally, therapeutic radiopharmaceuticals are designed for site specificity and based solely
upon physiological function of the target organ even if the actual location of the cancerous tumor is unknown. The
mechanism of localization of the radiopharmaceutical in a particular target organ depends upon processes as varied
as antigen antibody reactions, physical trapping of particles, receptor site binding, and transport of a chemical
species across a cell membrane, among others.
Ideally, the radiopharmaceutical will cause minimal or tolerable damage to healthy, adjacent tissue. However, a
variety of factors related directly to the physical and chemical characteristics of the radiopharmaceutical make this
goal difficult to achieve. Research will continue to address problems related to effi cient radiopharmaceutical
delivery to the target site. For example, the residence time of radioactivity at the target site, the in vivo catabolism
and metabolism of the drug, and the optimization of relative rates of radiolabeled drug or drug metabolite clearance
from the target site are factors to be determined. Development of an effective radiopharmaceutical for therapeutic
use is a complex, difficult undertaking

The amount of radiation absorbed by body tissue in which a radioactive substance resides is called the radiation
dose. Traditionally, this is measured in rad (radiation absorbed dose); 1 rad = 100 ergs of energy absorbed by 1 g of
tissue. The Gray (Gy) is the international unit of absorbed dose, equal to 1 joule of energy absorbed in 1 kg of tissue;
that is, 1 Gy = 100 rad. Radiopharmaceutical doses are dispensed to patients in units of activity, typically mCi or
µCi. Traditional therapeutic agents are dispensed according to weight-based calculations to determine appropriate
activity. The pharmacist remains responsible to ensure that the proper prescribed dose is prepared and dispensed.
Because of the nature of radiopharmaceuticals, the amount of radioactivity in the unit dose at the time of preparation
must be sufficient to allow for decay of radioactivity before the product is administered.
The three main types of radiation decay are alpha particles, beta particles, and gamma photons (or gamma rays). Of
the three types, alpha particles have the largest mass and charge of radiation, consisting of two protons and two
neutrons, identical with the helium nucleus. As an alpha particle loses energy, its velocity decreases. It then attracts
electrons and becomes a helium atom. Most alpha particles are unable to pierce the outer layers of skin or penetrate
a thin piece of paper.
However, because the charge is large, it does cause a great deal of damage to the immediate area by breaking down
DNA. Beta particles may be either electrons with negative charge, negatrons, or positive electrons, positrons. These
two particles, − and +, have a range of more than 100 feet in air and up to about 1 mm in tissue. Beta particles are
not as destructive as alpha particles, but they can be used therapeutically. The beta particle possesses a lot of kinetic
energy, thousands to millions of electron volts. Nuclear medicine depends mostly on radiopharmaceuticals that
decay by gamma emission. Gamma rays are electromagnetic vibrations comparable with light but with much shorter
wavelength. Because of their short wavelength and high energy, they are very penetrating.
DIAGNOSTIC IMAGING
131
Some radiopharmaceuticals are formulated to be placed within a target organ. I is taken up actively by thyroid
cells following absorption into the blood stream after oral administration of a capsule or solution. The extent of
uptake of the dose by the gland helps assess thyroid function, or an image of the gland can be obtained after
administration.
131 131
Alternatively, when I was labeled with orthoiodohippuric acid ( I-orthoiodohippurate, or OIH) and
intravenously injected, kidney tubules would actively secrete this agent into urine. Measuring the time course of
activity over the kidney with a gamma camera and plotting the rate of radioactivity accumulation and removal
versus time yields a measure of kidney function. This dynamic study, termed a renogram, is particularly useful to
assess renal function in patients with transplanted kidneys. The visualization of the entire kidney anatomically is
known as a pyelogram.
THERAPEUTIC USE OF RADIOPHARMACEUTICALS

Therapeutic radiopharmaceuticals are radiolabeled molecules designed to deliver therapeutic doses of ionizing
radiation to specific disease sites, such as cancerous tumors, with high specificity in the body. The design of each
radiotherapeutic agent requires optimizing the balance between specific targeting of the disease, such as a cancerous
tumor, and the clearance of radioactivity from nontarget radiosensitive tissues; it is also necessary to consider the
physical radioactive decay properties of the radionuclide. As mentioned earlier, difficulties in the design and
development of a highly selective radiolabeled drug carrier include drug delivery, maximizing the residence time of
radioactivity at target sites, in vivo catabolism and metabolism of the drug, and optimization of relative rates of the
radiolabeled drug or metabolite clearance from nontarget sites, among others.
Unsealed source radiolabeled agents have been used for treatment of cancers for more than five decades. Thyroid
131 32
disease has been treated with sodium iodide, I; polycythemia vera can be treated with sodium phosphate, P;
32 153 186
peritoneal effusions can be treated with chromic phosphate, P; and 89Sr-chloride, Sm-EDTMP, and Re-
HEDP are used for pain relief associated with metastatic bone lesions. The intent is to use beta radiation to destroy
diseased tissue selectively. Thus, a minimum sufficient dosage must be administered although this dose can be much

131
larger than doses for diagnostics. In the case of I, the therapeutic dose is 5 to 10,000 times the dose used to assess
organ function.
The major indications for radioiodine therapy include hyperthyroidism (diffuse toxic goiter, or Graves disease and
toxic multinodular goiter) and eradication of metastatic disease (thyroid cancer).
TECHNETIUM-99 M (99MTc)
99 m
Technetium- (99mTc) possesses a relatively short half-life of 6 hours, which allows administration of higher
amounts of activity for faster and clearer images while exposing the patient to a low radiation dose.
99mTc has also been used as a radiolabel for monoclonal antibodies ( MABs) because of its wide availability in
nuclear pharmacies and because it is relatively inexpensive and easy to obtain. It provides low radiation dosimetry
and highly efficient detection of photons by planar scintigraphy
99m
Tc sulfur colloid is used for imaging areas of functioning reticuloendothelial (RE) cells in the liver, spleen, and
bone marrow (13)
STRONTIUM-89 CHLORIDE (89Sr)

89
Strontium-89 Chloride ( Sr) (Metastron) is a sterile, nonpyrogenic aqueous solution for intravenous use and
contains no preservative. It decays by beta emission, with a physical half-life of 51 days. This beta emission is very
harmful to skeletal tissue, and thus its clinical use is reserved for bone pain palliation associated with primary bone
tumors and metastatic involvement (blastic lesions). An advantage of 89Sr is that it is retained and accumulated in
metastatic bone lesions much longer and in significantly greater concentration than in normal bone.












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CUC Integrated Pharmaceutics II Lecture Note ͟͢͠͞

Chapter one: Semisolid dosage forms

Anatomy and physiology

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The subcutaneous tissue

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The subcutaneous fat (subcutis, hypoderrri) provides

The skin appendages

Rational approach to drug delivery to and via the skin

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Stratum corneum treatment

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Skin appendage treatment

Viable epidermis and dermis treatment

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Drug examples include topical steroidal and nonsteroidal anti-inflammatory agents;

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Systemic treatment via transdermal absorption

Ideal molecular properties for drug penetration

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Silicones Dimethicones, or dimethyl polysiloxanes, have properties similar to hydrocarbon bases.

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To minimize drug precipitation, a formulator may include a less volatile, water-miscible

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Cosmetic or aesthetic criteria for dermatological formulations

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Physicochemical criteria for dermatological formulations

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Chapter Two: SUPPOSITORIES AND PESSARIES/ RECTAL DRUG DELIVERY

Anatomy and physiology of the rectum

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Absorption of drugs from the rectum

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The vehicle (suppository base)

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Determination of the Amount of Base Required

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Rectal formulations other than suppositories

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VAGINAL DRUG DELIVERY

Formulation of vaginal dosage forms

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Chapter Three: POWDERS AND GRANULES

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PHYSICAL PHARMACY CAPSULE 6.1

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Other methods of particle size determinations include elutriation, centrifugation, permeation,

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POROSITY, VOID, AND BULK VOLUME

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Porosity is Void x 100

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