pharmaceutics iii pt 506 - elearning.mti.edu.eg

Pharmaceutics III PT 506

Pharmaceutics and Drug

Manufacturing Department

Reaction Kinetics & Drug Stability

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Reaction kinetics

Reaction: The interaction between reactants to give products.

Reaction Kinetics: also known as chemical reaction kinetics or reaction rate study:

The study dealing with the rate of chemical and physical reaction and the factors which

influence the reaction rate

Why reaction kinetics is important in pharmacy??

1- Studying the stability and incompatibility.

2- Studying the rate of dissolution of solid dosage form which is important to study

the rate of the absorption process.

3- Studying the rate of pharmacokinetic processes such as absorption, distribution

and elimination of drug

4- Prediction of shelf life of drug.

5- Prediction of optimum storage conditions.

6- Prediction of reaction mechanism & factors affecting it.


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Reaction rate

Reaction rate is the change in concentration of a reactant or a product as a function of

time or the velocity with which a reaction or a process occurs.

Consider the following chemical reaction

Drug A → Drug B

The rate of forward reaction is expressed as:

-dA/dt

-ve sign = concentration of drugs A decreases with time.

Here dA is the small change in the concentration within a given time interval dt.

As the reaction proceeds, the concentration of the drugs B increases and the rate of

reaction can also be expressed as:

dB/dt

Experimentally, the rate of reaction is determined by measuring the decrease in

concentration of drugs A with time.


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Example: Formation and hydrolysis of ethyl acetate:

CH3COOH + C2H5OH CH3COOC2H5 + H2O

Rate of forward reaction is determined by measuring the decrease in conc. of reactants

(acetic acid / ethanol) with time or increase in conc. of products (ethyl acetate / water):

Rf = - = - = + = +

Rate of reverse reaction is determined by measuring the decrease in conc. of ethyl

acetate or water with time or increase in conc. of acetic acid or ethanol:

Rr = - = - = =

Reaction order

Concentration of drugs influences the rate of reaction or process which is called as the

order of reaction or order of process.

Order of a reaction is defined as the number of concentration terms on which the rate of

a reaction depends when determined experimentally.

Law of mass action

Law of mass action states that the rate of a reaction is proportional to the molar

concentrations of the reactants each raised to power equal to the number of molecules

undergoing reaction.

a A + b B →Product


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Rate α [A]a .[B]

b

Rate = K [A]a .[B]

b

Order of reaction = sum of exponents

Order of A = a and B = b

Then Overall order = a + b

N.B: The order of a reaction determines the way in which the concentration of a

reactant or reactants influences the rate of a chemical reaction.

Example

The reaction of acetic anhydride with ethyl alcohol to form ethyl acetate and water

(CH3 CO)2 O + 2 C2H5OH →2CH3 CO2 C2H5 + H2O

Rate = K [(CH3 CO)2 O] . [C2H5OH]2

Order for (CH3 CO)2 O is 1st order

Order for [C2H5OH]2 is 2nd order

Overall order of reaction is 3rd Order

Molecularity of the reaction

The molecularity of a reaction refers to the numbers of molecules, atoms, or ions

reacting in a elementary process to give the reactants.

If only one type of molecules undergoes a change in to yield the product, the product is

said to be unimolecular.


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If two molecules undergo a change to yield the product, the reaction is said to be

bimolecular.

Reaction that involves more than one step (complex reaction) may have different

molecularity and order of reaction.

Types of Order of reaction

The three commonly encountered rate process:

1. Zero order reaction

2. First order reaction

3. Second order reaction

Zero-Order Reaction

It is also called as constant rate process.

The reaction is said to be zero-order reaction, if the rate of reaction is independent of

the concentration i.e. the rate of reaction cannot be increased further by increasing the

concentration of reactants.

In this type of reaction, the limiting factor is something other than concentration.

dc/ dt= -Ko C = -Ko

Where

Ko = zero-order rate constant (in mg/mL.min)


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Rearrangement of the above equation yields:

dc= -Ko dt

Integration of this equation gives:

C - Co = - k0 t

or

C = Co - k0 t

Where Co = concentration of drug at t = 0 (initial concentration).

C = concentration of drug yet to undergo reaction at time t (remaining concentration at

time t).

N.B. K0 units: mg ml-1

year−1

A plot of C versus time results in straight line with slope equal to K.

The value of K indicates the amount of drug that is degraded per unit time, and intercept

of line at time zero is equal to constant


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Determination of t½

Let C = Co /2 and t½ = t

Substitute in equation; C = Co – k t

C = C0 at (t = t1/2)

C0 = C0 – kt1/2

kt1/2 = C0 - C0 = C0

t1/2 = Co/2k

Note: Rate constant (k) and t½ depend on Co

Determination of t0.9

Let C = 0.9 Co and t= t0.9

substitute in equation; C = Co –k t

C = 90% C0 = 0.9 C0

0.9 C0 = C0 - K t90%

K t90% = C0 – 0.9 C0 = 0.1 C0

t90% = 0.1Co/k


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Example

Drug X degrades by a zero-order process with a rate constant of 0.05 mg ml-1

year−1

at

room temperature. If a 1% weight/volume (w/v) solution is prepared and stored at room

temperature:

1. What concentration will remain after 18 months?

2. What is the half-life of the drug?

Answer

C0 = 1% w/v = 10 mg/ml; t =18 months = 1.5 year; k0 = 0.05 mg ml−1

year−1

1. C = C0 – k0t = 10 – (0.05 × 1.5) = 9.93 mg/ml

2. t1/2 = 0.5 C0/k0 = (0.5 × 10)/0.05 = 100 years

First order reaction

Whose rate is directly proportional to the concentration of the drugs undergoing

reaction i.e. greater the concentration, faster the reaction.

The most common pharmaceutical reactions e.g; drug absorption & drug degradation

First-order process is said to follow linear kinetics

dC/dt= - KC

Where K = first-order rate constant (time -1

)

Integrating above rate equation between initial concentration Co at t = 0 & C,

concentration after t=t, we obtain:


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ln C- ln Co= -Kt

Log C= Log C0 - k t/2.303

When this linear equation is plotted with ‘log C’ on vertical axis against ‘t’ on

horizontal axis, the slope of the line is equal to= -kt/2.303

N.K Units: year -1


Let t = t½ and C = C0 /2

substitute in Log C= Log C0 - k t/2.303

Log C = log C0 -

C = C0 at (t = t1/2)

log ½ C0 = log C0 -

= log C0 – log ½ C0

= log = log 2


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t1/2 =

t½= 0.693/k

K = 0.693 / t½


Let t = t0.9 C = 0.9 Co

substitute in: Log C= Log C0 - k t/2.303

t0.9=0.105 /k

k=0.105/t0.9

Examples

1- Ten (10) ml aqueous solutions of drug A (10% w/v) and drug B(25% w/v) are stored

in two identical test tubes under identical storage conditions at 37°C for 3 months. If

both drugs degrade by first-order, which drug will retain the highest percentage of

initial concentration?

(a) Drug A

(b) Drug B

(c) They will be the same.

Answer: both drugs will have the same percentages of initial concentration, as the

degradation process is first order

2. The concentration of drug X in aqueous solution drops by 10% per month when

stored at room temperature. If the degradation occurs by first order, what concentration


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will remain if a 5 mg/ml solution of the drug is stored under the same conditions for 3

months?

Answer: remaining concentration= 5 x 0.9x 0.9x0.9 = 3.65 mg/mL

3. A 5 gm/100 ml solution of drug X is stored in a closed test tube at 25°C. If the rate of

degradation of the drug is 0.05 day−1

, calculate the time required for the initial

concentration to drop to (a) 50% (half-life) and (b) 90% (shelf-life) of its initial value.

Answer: From the unit of rat constant (day -1), we can conclude that the degradation

process is first order, so:

(a)- t½= 0.693/K= 0.693/0.5= 13.9 days

(b) – t 0.9= 0.105/K= 0.105/0.5= 2.1 days

4. A 5 gm/100 ml solution of drug X is stored in a closed test tube at 25°C. If the rate of

degradation of the drug is 0.05 day−1

, calculate the time for the drug concentration to

degrade to 2.5 mg/ml.

Answer: t= 13.9 days

Second-Order Reaction

Rate depends on the product of two concentration terms.

When you have two components reacting with each other or one component reacting

with itself.

Example: 2HI = H2 + I2 , 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:


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Rate = dC/dt = k[HI][HI] = k[HI]2

dC/dt = -kC2

dC/C2 = -kdt

By integration : 1/C=1/Co+Kt

Units of K:

1/C = 1/Co + Kt K = (1/C - 1/Co) / t

K = M-1

. sec -1

i.e, K is dependent on initial drug concentration.

Derive equation for t½ and shelf life

Half life: t½ = 1 / KCo

Shelf life: t0.9 = 0.11 / KCo


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Pseudo-First Order Reaction

Pseudo first order reaction is defined as a reaction which is originally a second order,

but is made to behave like a first order reaction.

• In second order reaction, the rate depends on the concentration terms of two reactants.

Therefore the rate equation would be

dC/dt= K2[A] [B]

dC/ dt= K2 [A] constant= K1 [A]

Determination of order and rate constants

1. Substitution method [data plotting method]

Data accumulated in experimental kinetic study may be substituted in the integrated

form of the equation that describes the various reaction orders . Take three consecutive

points from the concentration versus time data. Calculate Δy/Δx for the first and

second points. The concentration is the Δy value, while time is the Δx value. Do the

same for the second and third point. If the reaction is zero order with regard to the

reactant, the numbers will be the same. If not, then calculate the slope for the inverse

concentration versus time data or natural log of the concentration versus time data.

2.Half-life method

• This method is based on the relationship between the initial concentration of the

reactant, the half life, and the reaction order.

• For zero-order reactions, t½ increases with increasing concentration.


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t1/2 = Co/2k

• For first-order reactions, t½ does not change with change in concentration.

t½= 0.693/k

3- Graphical Method

This pictorial method may be more reliable because deviations from the best fit line can

be easily observed. Conduct the kinetic experiment and collect the data on the time

course of changes in the concentration of the reactants. Plot the data on a graph paper as

per the general principles of each order.

Three plots are made. The first is concentration of the reactant versus time. The second

is of inverse concentration versus time, while the third is of the natural log of

concentration versus time. These graphs, respectively, show zero, first, and second

order dependence on the specific reactant.

• Decide which graph gives a better fit for a straight line.

Concentration against time …….. zero order reaction [if straight line]

log concentration against time ……. First order reaction [if straight line]

1/concentration against time …….. Second order reaction [if straight line].

Factors affecting the reaction rate

1) Temperature

2) Catalyst

3) Concentration effect

4) Chemical nature of the reactants

5) Phase and Surface Area


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1- Temperature

The higher the temperature the faster the reaction.

This is due to increased and more energetic collisions between reacting particles.

A 10 oC rise in temperature often results in a doubling of the reaction rate.

At a higher temperature more molecules have energy greater than the activation energy.

Arrhenius equation describes the effect of temperature on reaction rate.

K= A.e-Ea/RT

LogK= LogA- Ea/2.303 RT

where,

K is the reaction rate constant (Time-1

(sec-1

))

A is the Frequency factor = collision factor ( no. of collision / sec) (sec-1

)

R is the gas constant = 1.987 cal/ oK.mole.

T is the absolute temperature (oK)

Ea is the activation energy which is the energy required to activate reactant to give

product (the difference between the average energy of reactive molecules & of inert

molecules) (Cal/mole)

Graphical representation of Arrhenius equation:

LogK vs. (1/T) give straight line


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2- Catalyst

Catalysts is a substance that participates in a chemical reaction and increases the

reaction rate without undergoing a net chemical change itself.

This is due a lowering of the activation energy for the reaction.

Example: A solution of hydrogen peroxide (H2O2) decomposes in water so slowly.

Iodide ion acts as a catalyst for the decomposition of H2O2, producing oxygen gas.

3- Concentration effect

The higher the level of concentration (or pressure in gases) the faster the reaction.

This is due to increased collisions between reacting particles.

Example: Mixing sucrose with dilute sulfuric acid in a beaker produces a simple

solution.

Mixing the same amount of sucrose with concentrated sulfuric acid results in a dramatic

reaction that eventually produces a column of black porous graphite and an intense

smell of burning sugar


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4- Chemical nature of the reactants

During chemical reactions, chemical bonds are broken and new bonds are formed.

The nature (or type) of these chemical bonds - and how readily they are broken and

formed - plays a critical role in the rate of a reaction.

When the reaction involves primarily the exchange of electrons (ionized molecules),

reactions tend to be very rapid.

5- Phase and Surface Area

Surface area in solids:

The larger the surface area of a solid the faster the reaction. Finely divided substances

have much larger surface areas than large chunks of a solid. This is due to increased

collisions between reacting particles.


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Drug Stability

Drug stability is the capacity of the pharmaceutical dosage form to maintain the

physical, chemical, therapeutic and microbial properties during the time of storage and

uses by the patient.

USP defines stability of pharmaceutical product as, “extent to which a product retains

with in specified limits throughout its period of storage and use (i.e. shelf life).

Stability is: a measure of how a pharmaceutical product maintains its quality attributes

over time.

Shelf-Life

It is defined as the time required for the concentration of the reactant to reduce to 90%

of its initial concentration. Represented as t90

It is the time from the date of manufacture and packaging of the formulation until its

chemical or therapeutic activity is maintained to a predetermined level of labeled

potency and, its physical characteristic have not changed appreciably.

Zero order Ist order

t0.9 = 0.1 Co / k t0.9 = 0.105 / K

Adverse effects of instability of drugs

Loss of active drug (e.g. aspirin hydrolysis, oxidation of adrenaline).

Loss of vehicle (e.g. evaporation of water from o/w creams, evaporation of

alcohol from alcoholic mixtures).


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Loss of content uniformity (e.g. creaming of emulsions, impaction of

suspensions).

Loss of elegance (e.g. fading of tablets and coloured solutions).

Reduction in bioavailability (e.g. ageing of tablets resulting in a change in

dissolution profile).

Production of potential toxic materials (e.g. breakdown products from drug

degradation).

Types of Stability

1- Chemical

Each active ingredient retains its chemical integrity and labeled potency within the

specified limit.

2- Physical

The physical stability properties includes appearance, palatability, uniformity,

dissolution and suspendability are retained.

3- Microbiological

Sterility or resistance to microbial growth is retained according to specified

requirement.

4- Therapeutic

Therapeutic activity remains unchanged.


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5- Toxicologic

No significant increase in toxicity occurs.

Degradation Pathways

Definition

The condition or process of degrading or being degraded in which the formulation

declines to a lower quality, condition or level.

The incapacity or incapability of a particular formulation in a specific container to

remain within a particular chemical, microbiological, therapeutical, physical &

toxicological specification.

Types of Pharmaceutical Degradation

It can be divided into three major types:

1. Physical degradation

2. Chemical degradation

3. Microbiological degradation

Chemical Degradation Pathways

Chemical Degradation: It is the separation of chemical compound into elements or

simpler compounds or the change in the chemical nature of the drug.

1) Hydrolysis

2) Oxidation

3) Photolysis


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4) Decarboxylation

5) Isomerization

6) Polymerization

1- Hydrolysis

Splitting by water.

Drugs with functional groups such as esters, amides, lactones or lactams may be

susceptible to hydrolytic degradation.

It is probably the most commonly encountered mode of drug degradation because

of the prevalence of such groups in medicinal agents and the ubiquitous nature of

water.

The active drug undergoes decomposition with the solvent (water) present in

which the solvent acts as nuclophiles attacking the electropositive center in the

drug molecules.

It is usually catalyzed by hydrogen ion (acid) or hydroxyl ion (base).

Ester Hydrolysis

The hydrolysis of an ester into a mixture of an acid & alcohol essentially involves the

rupture of a covalent linkage between a carbon atom & an oxygen atom (acyl-oxygen

cleavage). Example of ester drugs: Aspirin, cocaine, procaine, nitroglycerine,

methyldopa.

Aspirin degrade into salicylic acid and acetic acid giving vinegar like odour.

R-COOR (ester) + H2O → R-COOH (acid) + R-OH(alcohol)


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Amid Hydrolysis

Amides are relatively stable than esters.

It involves cleavage of amide linkage to give an amine instead of alcohol as in

case of esters.

Acetaminophen, chloramphenicol, indomethacin and sulfacetamide all produce

an aminoacid through hydrolysis of their amide bond.

RCONHR(amide) + H2O → RCOOH + R-NH2(AMINE)

Protection against Hydrolysis

1) In liquid dosage form since, hydrolysis is acid or base catalyzed, an optimum PH

for max stability should be selected and the formulation should be stabilized at

this PH by inclusion of proper buffering agents.


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2) Hydrolysis of certain drugs such as benzocaine and procaine can be decreased by

the addition of specific complexing agent like caffeine to the drug solutions.

3) Addition of surfactants, addition of surface-active agents results into significant

improvement of drug stability.

4) This occurs due to the micelles formation. Surface active agents are of two types

cationic and anionic. Anionic micelles are more effective.

5) Hydrolysis susceptible drugs such as penicillin and derivatives can be prevented

by formulating them in the dry powder form for reconstitution or dispersible

tablets instead of a liquid dosage form such as solutions or suspensions.

6) Production of insoluble form of drug: Hydrolysis occurs only with that portion of

drug which is in aqueous solution. Ex: Hydrolysis can be minimized by by

making suspensions instead of solutions.

7) Other preventive steps such as:

Avoiding contact with moisture at time of manufacture.

Packaging in suitable moisture resistant packs such as strip packs

Storage in controlled humidity and temperature.

2- Oxidation

Removal of an electropositive atom, radical or electron (removal of hydrogen), or the

addition of an electronegative atom or radical (addition of oxygen).

Oxidation is controlled by environment i.e, light, trace elements, oxygen and oxidizing

agents.

Oxidation has two types:


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Auto-oxidation

Photo-oxidation

Auto- Oxidation

Oxidation in which the oxygen presents in the air is involved.

This process proceeds slowly under the influence of atmospheric oxygen e.g. Oil,

fats & unsaturated compound can undergo auto- oxidation.

The reaction between the compounds and molecular oxygen is required for

initiating the reaction.

Free radicals produced during initial reaction are highly reactive and further

catalyze the reaction produced additional free radicals and causing a chain

reaction.

Heavy metals such as copper, iron, cobalt, and nickel have been known to

catalyze the oxidative degradation.

Heat and light further influence the kinetics of oxidative degradation processes.

Photo-Oxidation

Oxidation in which removal of the electron is involved with out presence of O2. This

type is less frequently encountered

e.g. It occurs in adrenaline, riboflavin & ascorbic acid.

Steps invovlved in oxidation reaction

INITIATION: Formation of free radicals is taken place .

R--H → Rʹ + [H ]


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PROPOGATION: here the free radical is regenerated and react with more oxygen .

Rʹ + O2 → Rʹ--O2

Rʹ--O2 + RH → ROOH + Rʹ

HYDROPEROXIDE DECOMPOSITION

ROOH → ROʹ + OHʹ.

TERMINATION: free radicals react with each other resulting in inactive products.

Rʹ--O2 + X → Inactive product

RO2 + RO2 →Inactive product

Protection against Oxidation

1- Use of antioxidants: antioxidants are mainly of 3 types :

A-The first group probably inhibits the oxidation by reacting with free radicals.

Example – tocopheral , butylated hydroxyl anisole (BHA) , butylated hydroxyl toluene's

(BHT). Used in concentration: 0.001 – 0.1%.

B- The second group comprising the reducing agents, have a lower redox potential than

the drug or other substance that they should protect and are therefore more readily

oxidized.

Example –ascorbic acid and iso ascorbic acid, potassium or sodium salts of

metabisulfite.

C- The third group, they have little antioxidant effect by themselves but enhance the

action of true antioxidant


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Example -- Citric acid, tartaric acid, disodium edetate and lecithin.

2- Use of chelating agent: when heavy metals catalyze oxidation.

Example -- EDTA , citric acid , tartaric acid form complexes.

3- The presence of reducing agent:

Oxidation of pharmaceutical products can be retarded by the addition of reducing

agents they are equally effective against oxidizing agents and atmospheric oxygen.

e.g. potassium metabisulphites - sodium metabisulphites

4- Removal of oxygen:

By limiting the contact of drug with the atmosphere, those oxidative decompositions

dependent upon atmospheric oxygen may be often minimized.

5- The presence of surface active agent:

Oxidizable materials such as oil soluble vitamins essential oils and unsaturated oils

have been formulated as solubilized and emulsified products

6- Adjustment of pH:

Many of those oxidative decompositions involving a reversible oxidation reduction

process are influenced by the hydrogen ion concentration of the system.


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3- Photolysis

Exposure to light cause substantial degradation of drug molecule.

When molecules are exposed to electromagnetic radiation they absorb light (photons)

at characteristic wavelength which cause increase in energy which can:

Cause decomposition.

Retained or transferred.

Be converted to heat .

Result in light emission at a new wavelength (fluorescence , phosphorescence).

N.B. Natural sun light lies in wavelength range (290- 780nm) of which only

higher energy (UV) range (290 --320) cause photo degradation of drugs.

Example of phototoxic drugs: Furosemide , acetazolamide , cynocobalamine .

Example:

Sodium nitropruside in aqueous solution (which is administered by IV infusion for

management of acute hypertension ).

If protected from light it is stable to at least 1year.

If exposed to normal room light it has a shelf life of 4 hrs.

Protection against photolysis

1. Use of amber colored bottles.

2. Storing the product in dark, packaging in cartons also act as physical barrier to light.


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3. Coating of tablets with polymer films.

4- Decarboxylation

Elimination of CO2 from a compound.

e.g. -When sol. Of NaHCO3 is autoclaved,.

- autoclaving the tuberculostatic agent sodium aminosalicylate

5- Isomerization

Conversion of an active drug into a less active or inactive isomer having same structural

formula but different stereochemical configuration.

Types: Optical isomerization

Geometrical isomerization

6- Polymerization

Combination of two or more identical molecules to form a much larger and more

complex molecule.

e.g. Degradation of antiseptic formulations and aldehydes is due to polymerization.


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Stability Studies

Stability testing is used to:

1. Provide evidence as to how the quality of the drug product varies with time.

2. Establish shelf life for the drug product.

3. Determine recommended storage conditions.

4. Determine container closure system suitability.

5. Safety point of view of patient.

6. Economic considerations

7. Essential quality attribute.

Types of Stability Studies

Long-Term (Real-Time) Stability Testing

Stability evaluation of the physical, chemical, biological and microbiological

characteristics of a drug product through the duration of the shelf life

Accelerated stability Testing

Studies designed to increase the rate of chemical degradation or physical change(s) of a

drug product by using exaggerated storage conditions with the purpose of monitoring

degradation reactions.

It is used to evaluate the impact of short term excursions and predicting the shelf-life

under normal storage conditions.


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The design of accelerated studies may include elevated temperature, high humidity and

intense light.

Methods of accelerated stability testing in dosage forms

1- Tests at elevated temperature:

Drug liquid preparation stored at 50, 60, 70, 85,100 and 121˚c.

Also study is performed at room temperature and / or refrigerator temperature.

Sampling:

- First year- 3 month interval - Second year- 6 month interval

Four climatic zones:

Temperate zone 21˚c/45%RH Mediterranean zone 25˚c/60%RH

Tropical zone 30˚c/70%RH Desert zone 30˚c/35%RH

2- Tests at high intensity of light:

Drug substances which fade or darken on exposing to light can be controlled by using

amber glass or opaque container.

This study is done by exposing drug substance to 400 & 900 (FC/foot candle) of

illumination for 4 & 2 weeks to light and another sample is examined protected from

light.

e.g. cycloprofen becomes very yellow after five days under 900 foot candles of light.

3- Tests at high partial pressure of oxygen:


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Sensitivity of the drugs to atmospheric oxygen must be evaluated from which it should

be packed in inert atmospheric condition with antioxidants is decided.

Here, high oxygen tension plays important role to investigate stability.

Usually, 40% of oxygen atmosphere allows for rapid evaluation.

Results should be correlated with inert & without inert condition.

4- Tests at high relative humidity:

Presence of moisture may cause hydrolysis and oxidation.

These reactions may accelerated by exposing the drug to different relative humidities.

Control humidity by Lab desiccators

Closed dessicators are placed in an oven to provide constant temperature.

ICH Guidelines on Stress Testing


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Drug-excipient interaction

Pharmaceutical dosage form is a combination of active pharmaceutical ingredients

(API) and excipients. Excipients are included in dosage forms to aid manufacture,

administration or absorption. Although considered pharmacologically inert, excipients

can initiate, propagate or participate in chemical or physical interactions with drug

compounds, which may compromise the effectiveness of a medication.

Mechanism of drug-excipients interaction

Exact mechanism of drug excipients interaction is not clear. Drug-excipients interaction

occurs more frequently than excipient-excipient interaction. Drug-excipients interaction

can either be beneficial or detrimental, which can be simply classified as:

1. Physical interactions

2. Chemical interactions

Physical interactions

It is quite common, but is very difficult to detect. A physical interaction doesn’t involve

any chemical changes. Physical interaction can either be beneficial or detrimental to

product performance.

An example of a physical interaction between an API and an excipient is that between

primary amine drugs and microcrystalline cellulose. When dissolution is carried out in

water a small percentage of the drug may be bound to the microcrystalline cellulose and


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not released. For high-dose drugs, this may not be a major issue, but for low dose drugs

it can lead to dissolution failures.

A general example of a physical interaction is interactive mixing. In this smaller

particles (typically the APIs) interact with the surface of the larger carrier particles

(typically the excipients) through physical forces. In this way we obtain a more

homogenous powder blend. After the medicine, e.g., a tablet has been administered to

the patient, the aqueous environment of the gastrointestinal tract (GIT) either causes the

smaller API particle or other carrier particles to dissolve or causes the surface

interactions to change to allow the smaller particles to be released from the larger

carrier particles.

Chemical interactions

Chemical interaction involves chemical reaction between drugs and excipients or drugs

and impurities/ residues present in the excipients to form different molecules. Chemical

interactions are almost detrimental to the product because they produce degradation

products.

Different types of chemical drug-excipients interaction have been reported such as:

Chemical interactions between drug and excipients.

Primary amine group of chlorpromazine undergoes Maillard reaction with glycosidic

hydroxyl group of reducing sugar dextrose to form imine, which finally breakdown to

form Amidori compounds.


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Another example is the release of diclofenac sodium from matrix tablet was inhibited

by polymer chitosan at low pH, most possibly via formation of ionic complex between

diclofenac sodium and ionized cationic polymer.

Suspending agents such as sodium alginate dissolve in water to form large negatively

charged anions, co-formulation in aqueous systems with drugs such as neomycin and

polymixin (active mioties of which are positively charged) result in precipitation.

Interaction of drug with excipient residues/ impurities

Exicipients are not exquisitely pure. In common with virtually all materials of minerals,

synthetic, semi-synthetic or natural origin manufacture involves using starting

materials, reagents and solvents. Residues invariably remain after isolation.

Low levels of residues may have a greater impact than might be expected, however-

particularly where the ration of excipient to drug is very high, or where the residue has

low molecular weight or acts as a catalyst.

Dextrose is widely used as tonicity modifier in the parenterals dosage form and it is

used as nutrition solution. Sterilizations by autoclaving of such parenteral preparations

containing dextrose can cause isomerization of dextrose in fructose and formation of

aldehyde (5-hydroxymethyl furfuraldehyde), which can react with primary amino group

to form shiff base and colour development.

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36

Powders & granules

37

Solid oral dosage forms

Medicinal substances are most frequently administered orally, by means of solid

dosage forms, such as tablets and capsules. Large scale production methods used

for their manufacture require the incorporation of other materials, in addition to the

active ingredients. These additives are usually included in the formulation to

facilitate handling, enhance the physical appearance, improve stability, and aid

in the delivery of the medicament to the blood stream after administration. These

materials, as well as the employed production methods, have been shown to

potentially influence the absorption and /or bioavailability of the drugs.

Powders and Granules

•Powder : a solid material in a finely divided state, having equivalent diameter less

than 1000 um.

• Granules : are powders agglomerated to produce larger free flowing particles

which may have overall dimensions greater than1000 um.

Advantages of powdered and granulated products: -

1. Solid preparations are more chemically stable than liquid ones as they have

longer shelf life.

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38

2. They are convenient form in which drugs with a large dose are dispensed (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.

Disadvantages of powders and granules: -

1. Bulk powders or granules are less convenient for the patient to carry than

small container of tablets or capsules

2. The masking of unpleasant tastes may be a problem with this type of

preparation.

3. Bulk powders or granules are not suitable for administering potent drugs

with a low dose

4. They are not suitable for administration of drugs which are inactivated in, or

cause damage to, the stomach

Powders and granules as dosage form

Powders and granules can be used to prepare other formulations, such as solutions,

suspensions, capsules, and tablets.

• Simple powder: powdered drug on its own which can be a dosage form for oral

administration.

• Compound powder: the powdered drug may be blended with some additives.

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39

Powdered and Granulated Products are Traditionally Dispensed as

1. Bulk powders or granules for internal use.

2. Divided powders or granules for internal use.

3. Dusting powders for external use.

4. Insufflations for administration to ear, nose or

throat.

5. Antibiotic syrups to be reconstituted before

use.

6. Powders for reconstitution into injection

Powders for Internal Use

The powder may be presented as:

1. Undivided powders (bulk powders).

2. Divided powders (individually wrapped doses).

• Particle size of powder is restricted by BP where powders for oral use must

be moderately fine or fine powder.

• Comminution is the process of particle size reduction. (Trituration: on small scale

it’s done with a pestle and mortar)

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40

Classification of Powders for Internal Use:-

1. Bulk Powders

2. Individually Wrapped Powders

3. Bulk Granules

4. Divided Granules

1. Bulk Powders

Useful for non-potent, bulky drugs used in large doses.

e.g., antacids, magnesium trisilicate and chalk, as present in Compound

Magnesium Trisilicate Oral Powder, compound kaolin powder. It is rarely seen

nowadays because the dosage form is inconvenient to carry and there are possible

inaccuracies in measuring the dose. e.g. dietary food supplements.

2.Individually Wrapped Powders

Advantages:

1. It can be used for potent drugs.

2. Convenient dosage forms for children's doses of drugs which are not

commercially available at the strength required as levothyroxine ibuprofen.

They are commercially available sealed sachets of powders as :Paramax

(paracetamol and metoclopramide), and oral rehydration sachets.

Disadvantages:

1- Possibility of ingredients decomposition if they were hygroscopic,

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41

2- volatile or deliquescent due to paper wrapping.

To overcome this problem modern packaging materials of foil and plastic are used

because they offer superior protective qualities. e.g. Effervescent powders Such

powders contain, for example, sodium bicarbonate and citric acid which need to be

protected from moisture during manufacture and on storage to prevent the reaction

occurring prematurely.

3.Bulk Granules

Bulk powders vary in their particle size, so they tend to segregate either on storage

in the final container or in the hoppers of packaging machines so there are No dose

uniformity. This can be prevented by granulating the mixed powders. Medicaments

to be used in this form are those with low-toxicity, high-dose drugs.

e.g. Methylcellulose Granules

4. Divided Granules

These are granulated products in which quantity sufficient for one dose is

individually wrapped. As individually wrapped powders modern packaging

materials of foil and plastic are used because they offer superior protective

qualities especially if the ingredients are volatile or deliquescent. e.g., Effervescent

granules.

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42

Shelf Life and Storage of Internal Powders:-

Extemporaneously prepared powders should have an expiry of between 2 and 4

weeks. Proprietary powders often have a longer shelf life because of the protective

packaging. Protective packaging is also useful for hygroscopic, deliquescent, or

volatile powder when storage must be airtight and moisture proof.

Containers for Internal Powders: -

Extemporaneously prepared individually wrapped powders and Proprietary

powders are placed in individual sachets, which are moisture proof is often

dispensed in a paper board box.

Bulk powders are packed in an airtight glass or plastic jar.

A 5mL spoon should also be supplied

Special label and advise for internal powders

Powders are usually mixed with water or another suitable liquid before taking,

depending on their solubility. Powders for babies or young children can be placed

directly into the mouth on the back of the tongue, followed by a drink to wash

down the powder.Bulk powders should be shaken and measured carefully before

dissolving or dispersing in a little water and taking.

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43

Powders for External Use

Dusting Powders

It’s present as fine powder. It may be dispensed as single dose or multi-dose

preparations. They should not be used where there is a likelihood of large volumes

of exudates, as hard crusts will form. usually, Zinc oxide and starch are added to

formulation to absorb moisture and talc is used for lubricant properties.it uses to

treat a variety of skin conditions. e.g. Antifungal powders for athlete's foot. Talc

dusting powder for the prevention of skin irritation

Sterilization of dusting powders

Talc, kaolin and other natural mineral materials are liable to contamination with

bacteria such as Clostridium tetani .(Sterilization is done by dry heat or the final

product should be sterilized).e.g. of official powders: zinc oxide dusting powder

and talc dusting powder.e.g. of proprietary powders: Canesten Powder

(clotrimazole) and daktarin (miconazole) are used as antifungal agents.

Shelf Life and Storage

If packaged and protected from the atmosphere, they remain stable over a long

period of time. Extemporaneously prepared products have an expiry of 4 weeks .

Containers

may be packed in glass, metal or plastic containers with a sifter-type cap.

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Other types of Powders

1. Insufflation’s powder

2. Dry Powder Inhalation

3. Powder for Oral Antibiotic Syrups

4. Powders for Injection

1) Insufflation’s powder

Definition.: medicated powders which are blown into regions such as the ear, nose

and throat using an insufflator.

Advantage of Insufflation’s powder:

potent drugs are now presented in this way because they are rapidly absorbed when

administered as a fine powder via the nose.

Disadvantages of Insufflation’s powder:

1. Inelegant and less convenient to apply than other topical preparations.

2. Not usually used for systemic action as not all doses may reach systemic

circulation (difficult to ensure that the same dose was delivered on each occasion.

2) Dry Powder Inhalers

This dosage form is one of the most effective methods of delivering active

ingredients to the lung for the treatment of asthma and chronic obstructive

pulmonary diseases.

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45

3) Powders for Injection

in ampoules or vials. Sufficient diluent, e.g. sterile water for injection, is added

from a second ampoule to produce the required drug concentration.

4) Oral Antibiotic Syrup

Useful for drugs which are physically or chemically unstable when formulated as

a solution or suspension. to overcome the instability problem: manufacture.the dry

ingredients of the intended liquid preparation in a suitable container in the form of

powder or granules. Once it is reconstituted, the patient is warned of the short

shelf-life. e.g. Amoxicillin Oral Suspension. Also, it used for medicaments that are

unstable in solution. They must be reconstituted immediately prior to use. They are

presented as sterile powders

Reasons for producing Free Flowing Powder:

1. Uniform feed from bulk storage containers or hoppers into the feed

mechanisms of tableting or capsule filling equipment which lead to tablet

weight uniformity.

2. Improves weight uniformity (produce tablets with more consistent physico-

mechanical properties).

3. Uneven powder flow → excess entrapped air within powders → capping or

lamination.

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46

4. Uneven powder flow → increase particle’s friction with die wall causing

lubrication problems and increase dust contamination risks during powder

transfer.

Particle Properties Adhesion and Cohesion

Cohesion: tendency for solid particles to stick to themselves (occurs between like

surfaces).

Adhesion: tendency for solid particles to stick to other solid surfaces as hopper

wall (occurs between unlike surfaces).

Cohesive forces are van der Waals forces which increase as particle size decreases

and vary with changes in relative humidity.

Cohesion provides a useful method of characterizing the frictional forces acting

within a powder bed to prevent powder flow.

Characterization of Powder Flow: -

A. Indirect Methods

1. Angle of Repose

2. Shear Cell Determination

3. Bulk Density Measurements

B. Direct method

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47

A. Indirect Methods

1. Angle of Repose

Is the maximum angle possible between the surface of a pile of powder and the

horizontal plane. The sample is poured onto a horizontal surface and the angle of

the resulting pyramid is measured. The user normally selects the funnel orifice

through which the powder flows slowly and reasonably constantly.

Free-flowing powders will tend to lower angles of repose.

Powders with angles of repose greater than 40° have unsatisfactory flow properties

• Angles close to 20° correspond to very good flow properties.

• tan Ө = h / r.

• Disadvantages of using Angle of repose:

1. The different methods may produce different values for the same powder.

2. Different angles of repose could be obtained for the same powder, owing to

differences in the way the samples were handled prior to measurement.

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The relationship between angle of repose and flowability: -

Flow property Angle of repose (degrees)

Excellent 25 - 30

Good 31- 35

Fair – aid not needed 36 - 40

Passable – may hang up 41- 45

Poor – must agitate, vibrate 46 - 55

Very poor 56 - 65

Very, very, poor > 66

Methods of Determining Angle of Repose:

1. Fixed height and Fixed base cone methods

• The angle of repose is formed by permitting powder to drop through a funnel

onto a fixed, vibration-free base. The height of the funnel is

varied during the test to carefully build up a symmetrical cone of powder.

Typically, the funnel height is maintained approximately 2 to 4cm from the top of

the powder pile as it is being formed to minimize the impact of falling powder on

the tip of the cone.

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49

• Alternatively, the funnel could be kept fixed while the base is permitted to vary

as the pile forms.

2. Shear Cell Determination

Powder is loaded into the cell and then compressed with a defined force. After

compression, the operator measures the force needed to shear

through the sample

Principle: characterize flowability from the behavior of powder in a shear cell by

determine the flow factor (f.f) of powder. The relationship between flow factor and

powder flowability is shown in the following table :

f.f. value Flow descriptor

>10 Free flowing

4 -10 Easy flowing

1.6 – 4 Cohesive

< 1.6 Very cohesive

3. Bulk Density Measurement

It depends on particle packing and changes as the powder consolidates. A

consolidated powder is more resistant to flow than a less consolidated one. The

ease with which a powder consolidates, can be used as an indirect method of

quantifying powder flow.

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The bulk density =

The weight of particles composing the bed of powder

volume of the bed (gm/cm3).

Hausner Ratio and Carr Index

A volume of powder is filled into a graduated glass cylinder and repeatedly tapped

for a known duration. The volume of powder after tapping is measured and a

calculation performed to calculate the Hausner Ratio or the Carr Index

(%).Cohesive powders have a high Hausner Ratio and Carr Index.

Hausner ratio = Df /D0

D0 = initial bulk density (fluff or poured bulk d.)

Df = final bulk density

Hausner ratio was related to interparticle friction: The powder with low

interparticle friction, such as coarse spheres, had ratios of approximately 1.2,

whereas more cohesive, less free-flowing powders such as flakes have Hausner

ratios greater than1.6.

Percent compressibility, according to Carr:

% compressibility = (Df - D0) / Df x100.

Relationship between powder flowability and % compressibility is shown in the

following table:

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51

% Compressibility Flow description Hausner ratio

< 10 Excellent flow 1.00 -1.11

11 – 15 Good 1.12 -1.18

16 – 20 Fair 1.19 -1.25

21 -25 Passable 1.26 -1.34

26– 31 Poor 1.35-1.45

32– 37 Very poor 1.46 -1.59

> 37 Extremely poor > 1.6

B-Direct Methods

1. Hopper Flow Rate

2. Recording Flow Meter

1. Hopper Flow rate

Principle: measure the rate at which powder discharges from a hopper.

Procedure:

1. A simple shuts is placed over the hopper outlet and the hopper fill with powder.

2. The shutter is then removed, and time taken for the powder to discharge

completely recorded.

3. By dividing the discharged powder mass by this time, a flow rate is obtained

(gm/sec.).

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2. Recording Flow meter

• Like Hopper Flow rate except those powders allowed to discharge from a hopper

or container on to a balance.

• If analogue balances is used then a chart recorder is used to produce a permanent

record of increase in powder mass with time.

• Signal from the balance is digitized and processed by a microcomputer.

Improvement of Powder Flowability

Powder flow can be improved by different method

1. Particle’s size and Distribution Particle

2. Shape and texture

3. Surface forces

4. Flow activators

1-Particle’s size and Distribution Particle

Coarse particles are more preferred than fine ones as they are less cohesive. An

optimum size for free flow exists when using coarse particles. The size distribution

can also be altered to improve flowability by removing a proportion of the fine

particle fraction or by increasing the proportion of coarser particles, such as occurs

in granulation

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2- Shape and texture

a) Particle’s Shape: Generally, more spherical particles have better flow

properties than more irregular particles. Spherical particles are obtained by

spray drying, or by temperature cycling crystallization.

b) Particle's texture: particles with very rough surfaces will be more cohesive

and have a greater tendency to interlock than smooth surfaced particles

3.Surface forces

Reduction of electrostatic charges can improve powder flowability. Electrostatic

charges can be reduced by altering process conditions to reduce frictional contacts

(where powder is poured down, the speed and length of transportation should be

minimized). Moisture content of particle greatly affects powder’s flowability.

Adsorbed surface moisture films tend to increase bulk density and reduce porosity.

Hygroscopic powders should be stored and processed under low humidity

conditions

4.Flow activators (Formulation additives)

Flow activators are commonly referred as glidants. Flow activators improve the

flowability of powders by reducing adhesion and cohesion.

e.g. talc and magnesium stearate

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Granulation

Introduction: -

Granulation is the process employed in the pharmaceutical industry whereby

powder forms are made to bind together to form larger multiparticle entities or

granules. Bonds between the primary particles are formed by compression, or by

using a binding agent. Granulation is carried out for several reasons.

Many powders have particles of small size and irregular shape. They are cohesive

and do not flow well. Granulation leads to larger more homogenous particles with

better flow characteristics, improving the tablet making process.

Compacted granules occupy less volume/unit weight compared with powder and is

easier to store and ship.

Steps:

1. Initial dry mixing of powdered ingredients (to achieve uniform distribution of

each ingredient through the mixing.).

2. Granulation.

3. Packed (used as dosage form) or mixed with other excipients prior to tablet

compaction or capsule filling).

Reasons for granulation

1. Prevent segregation of the constituents of the powder mixture .

2. Improve flow properties of the mix.

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3. Improve compaction characteristics of the mix.

4. Other reasons are

i. modify or improve the drug release profile.

ii. The risk of caking of hygroscopic materials is reduced as the granules are

still able to absorb moisture but retain their ability to flow on account of the

large granule size, and

iii. Handling of toxic material is less hazardous than is the case with fine

powder.

iv. Improve the appearance of the tablet

v. Densify the material (Granules occupy less volume per unit weight, they are

more convenient for storage or shipment

vi. Ideally the granulated material should exhibit high mechanical strength and

be non-friable.

1. Prevent segregation of the constituents of the powder mix

Reasons for Segregation (demixing) are:

1. Differences in size.

2. Differences in density of the components of the mix.

3. Electrostatic charge due to constant friction among the mixed particles. Similar

charges repel particles from each other.

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The smaller and /or denser particles at the base of the container while the larger

and/or less dense ones above them. In ideal granulation: each granule will contain

all the constituents of the mix. in the correct proportion. It is important to control

particle size distribution of the granules Because although the individual

components may not segregate if there is a wide size distribution the granules

themselves may segregate.

2. To improve flow properties of the mix

Powders may be cohesive and don’t flow well due to their small size, irregular

shape, or surface characteristics. Poor flow will often result in a wide weight

variation within the final product owing to variable fill of tablet dies etc.

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Granules will be more isodiametric and larger that lead to improved flow

Properties

3. To improve the compaction characteristics of the mix

Applied to powders which are difficult to compact (even if compactable

adhesive (binder) is included in the mix). Granules of the same formulation are

easily compacted and produce stronger tablets. This is associated with the

distribution of the adhesive within the granule and depends on the method used

to produce the granule

Mechanisms of Granulation

Granules are formed by the binding together of powder particles. Sufficiency

strong bonds much be formed between particles so that they adhere and do not

break. There are five recognized bonds that form between particles: adhesive and

cohesive forces in the immobile liquid between particles interfacial forces in

mobile liquid films within granules formation of a solid bridge after subsequent

solvent evaporation. In a suitable formulation several different excipients will be

needed in addition to the drug

Diluents: to increase the bulk volume of powder and increase the size of the tablet.

e.g. lactose.

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Disintegrating agents: which are added to aid the break-up of the granule when it

reaches a liquid medium, e.g. on ingestion by the patient. e.g. starch.

Adhesives: in the form of a dry powder may also be added, particularly if dry

granulation is employed. e.g. gum and gelatin.

The ideal characteristics of granules include :

1. uniformity,

2. good flow,

3. compactibility.

Attractive forces between solid particles as presence of liquid not required,

mechanical interlocking of particles often between fibrous or flat particles.

There are two broad methods employed for granulating pharmaceutical

formulations: dry granulation and wet granulation.

Dry granulation

Dry granulation is used to form granules without using a liquid solution because

the materials to be granulated may be sensitive to moisture and heat. Forming

granules without moisture requires compacting and densifying the powders. In this

process the primary powder particles are aggregated under high pressure. Dry

granulation has fewer process stages than wet granulation. Compacting the powder

for dry granulation can be done either using a heavy-duty tabletting press, or the

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powder is squeezed between two counter-rotating rollers, in what is referred to as a

Chilson compactor, to produce a continuous sheet or ribbon of materials.

It is then compressed by roller compaction (slugging) for the first time. This results

in sheets of compressed material, which are then milled into granules of exactly the

agreed density, before being lubricated and compressed into the desired final form.

Roller compacted particle are usually dense, with sharp-edged profiles. When a

tablet press is used for dry granulation, the powders may not possess enough

natural flow to feed the product uniformly into the die cavity, resulting in varying

degrees of densification.

In dry granulation there are two types of irresistible attractive physical forces

between particles that cause them to bind them together

1. Electrostatic forces – there are generally weak but may cause cohesion when

the material is mixed initially.

2. Vand der Waals forces – these are stronger than electrostatic forces and they

increase as the inter-particulate distances decrease during the compression of

powders.

In dry granulation the pressure applied increases the contact area between the

adsorption layers of particles and decreases the inter-particulate distances, thereby

contributing to the final strength of the material. The pressure applied during dry

granulation may also melt low melting-point materials where the particles touch

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and high pressures are developed. When this happens, the particles will bind

together and crystallization may take place when the pressure is relieved.

Dry granulation techniques

Dry granulation operations do not use moisture or heat to process powders into

densified granules. The processes create granules by light compaction of the

powder blend under low pressures. The compacts so formed are broken up gently

to produce granules (agglomerates). This process is often used when the product to

be granulate is sensitive to moisture and heat. In dry granulation process the

powder mixture is compressed without the use of heat and solvent.

Main dry granulation techniques are :

1. Slugging

2. Roller Compaction

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Slugging:-

Steps in dry granulation (Slugging) :

1- Milling of drugs and excipients

2- Mixing of milled powders

3- Compression into large, hard tablets to make slug

4- Screening of slugs.

The slugging process is still used today by only a few manufacturing firms that

have old pharmaceutical formulation processes.

Schematic diagram of dry granulation and two different techniques. Method I is

roller compaction and Method II is slugging.

Roller Compaction (Chilsonator)

This technology is well suited for dry granulation in the area of modern

development of active pharmaceutical ingredients in pharmaceutical plants.

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Process Description

1. The powder is fed down between the rollers from the hopper which contains a

spiral auger (screw).

2. The screw serves to de-aerate the powder and maintain a constant flow of the

powder into the compaction rolls.

3. The pressure between the nips of the rolls is regulated by hydraulic means.

4. The product obtained is in the form of compressed sheets which can be broken

up into granules of the desired size.

Therefore, materials those normally require slugging two or more times can be

granulated by a single pass through the “Chilsonator”

Schematic of the Chilsonator roller compaction process

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63

Advantages of dry granulation

1. No heat or solvent is required so it is used for heat sensitive and/or moisture

sensitive material.

2. It improves the disintegration of tablet. Disintegration is usually more rapid,

since the disintegration power of starch is not diminished by the presence of

adhesives used in moist granulation.

3. It improves the solubility of materials tending to float.

4. No- migration of active ingredients or colors.

5. It is of the value in preparing effervescent tablets, since the dried acid and alkali

remain fully dry and active until the tablet is immersed in water when used,

6. It uses less equipment’s and space.

7. It eliminates the need for binder solution, heavy mixing equipment and time-

consuming drying step required for wet granulation.

Disadvantages of dry granulation

i) It requires a specialized heavy duty tablet press to form slug

ii) It does not permit uniform colour distribution as can be achieved with wet

granulation where the dye can be incorporated into binder liquid.

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iii) The process tends to create more dust than wet granulation, increasing the

potential contamination.

Wet granulation

In wet granulation, granules are formed by the addition of a granulation liquid

(usually an aqueous solution) onto a powder bed which is under the influence of an

impeller (in a high-shear granulator), screws (in a twin-screw granulator) or air (in

a fluidized bed granulator). Agitation of the particles along with the added liquid

produces bonding between the primary powder particles to produce wet granules.

The liquid must be volatile so that it can be removed by drying and typically water,

ethanol or isopropanol is used either alone or in combination. Aqueous liquids are

safer to use than organic solvents. Although water may initially bind particles

together, when it evaporates the powder may disintegrate so a binder is added,

which is a type of glue. Typically, povidone (polyvinyl pyrollidone (PVP) is used.

Once the water or solvent evaporates from the mixture, the binder locks powder

particles together in granules which may then be milled to the desired dimensions.

The process can be very simple or very complex depending on

1. The characteristics of the powders,

2. The final objective of tablet making, and

3. The equipment that is available.

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In the traditional wet granulation method, the wet mass is forced through a sieve to

produce wet granules which is subsequently dried.

The main mechanism in wet granulation

The mechanism of wet granulation begins when liquid is added to the powder

causing a thin and immobile film of liquid to form between particles. This causes

an effective decrease in inter-particulate distance and an increase in contact area

between particles. The shortening of the inter-particulate distance increases the

Van der Waals forces of attraction. More liquid is usually added in wet granulation

to form a mobile liquid film.

Wet granulation Methods

1) High shear granulation

2) Rotary granulator

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3) Fluid bed granulation

4) Extrusion - spheronization

5) Spray drying

Extrusion – spheronization

Process Description:

1. mixing of ingredients to achieve a homogenous powder dispersion.

2. Wet massing to produce a sufficiently plastic wet mass.

3. Extrusion to form rod-shaped particles of uniform diameter.

4. Spheronization to round off these rods into spherical particles.

5. Drying to achieve the desired final moisture content.

6. Screening (optional) to achieve the desired narrow size distribution.

Advantages:

1. Ability to incorporate higher levels of active components without

producing excessively larger particles.

2. Applicable to both immediate and controlled release dosage form.

3. It’s more efficient than other techniques for producing spheres, yet it’s

more labor and time intensive.

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Spray drying granulation

It’s used for the conversion of a liquid, slurry, or low-viscosity paste to a dry solid

(free-flowing hollow spheres) in a single step. Granules produced are extremely

consistent in terms of particle size, bulk density and compaction behavior. So,

spray drying a suitable process for the production of directly compressible

excipients such as lactose, microcrystalline cellulose, and mannitol.

Process Description

a) Atomization of a liquid feed into fine droplets

b) Spray droplets mix with a heated gas stream.

c) Dried particles are produced by the evaporation of the liquid from the droplets.

d) Separation of the dried powder from the gas stream and collection of these

powders in a chamber.

Advantages:

1. Rapid process

2. Ability to be operated continuously

3. Suitable for heat sensitive product

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Spray drying granulation

Advantages of wet granulation

1. Cohesiveness and compressibility of the powder are improved.

2. It is used for high dosage drugs with weak compressibility.

3. It is used for small doses to avoid non-uniformity of mixing which occur if

direct compression is used.

4. The colorant is dissolved in the solvent and distributed uniformly, but in direct

compression, there is no uniform distribution of the color.

5. Wet granulation process prevent segregation and separation of particles.

Disadvantages of wet granulation

1.It is not used with heat and /or moisture – sensitive material.

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2. Migration of color (water – soluble colors) and this can be overcome by using

color lakes.

3. Cost is high because of long procedures and use number of expensive

equipment’s.

4. It is more time consuming especially the wetting and drying steps (it takes about

2 days)

5. It increase the incompatibility between ingredients.

6. It requires a large area with temperature and humidity control as it require many

steps.

7. Material loss during processing due to the transfer of materials from one unit

operation to another.

8. The presence of moisture may cause an increase in particle size and may cause

modification of crystal structure so increase disintegration time which lead to

decrease of dissolution of drugs.

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Tablets

71

Tablets

Solid dosage form comprises tablets and capsules constitute about 80% of all

dosage forms. They are used to produce systemic action.

Definition

A tablet is a unit dosage form of medication containing one or more drugs to which

excipients are added and compressed as granules or powder to a definite shape.

Advantages of tablets as dosage form:

1- Are convenient to use and elegant dosage form.

2- Availability in a wide range of types which offer a range of drug release rates

and duration of clinical effect.

3- Tablets may be formulated to release the drug at site within G.I.T. promoting the

absorption at this site. This could not be done by other dosage forms.

4- Formulation of tablets could contain more than one drug even if there is

incompatibility between each drug.

5- All classes of therapeutic agent may be administered orally.

6- Ease of masking bad taste by coating.

7- Tablets generally are non-expensive.

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8- Tablets are more stable chemically, physically, or microbiologically than other

dosage forms.

Disadvantages of tablets as dosage forms:

1- The manufacture of tablets requires many steps of operation and in

each step an increased product loss in manufacturing.

2- The drug absorption from tablets depends on physiological factors e.g.

gastric emptying rate and show patient variation.

3- The compression of some drugs is poor and may present problems in

the manufacture

4- The problem to administer tablets to children and elderly peoples due

to difficulty in swallowing. This problem is solved by using effervescent and

chewable tablet

Types of tablets

1- Conventional compressed tablets (C.T.)

These tablets are designed to provide rapid disintegration and hence rapid drug

release and represent a significant proportion of tablets clinically used. These

tablets ore manufactured by compressing granules or powders that containing

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the drug. On administration by the patient this tablet will disintegrate within

G.I.T. allowing the drug to dissolve in the gastric fluid and absorbed.

2- Multiple compressed tablets (M.C.T.)

These are tablets composed of at least two layers and there are two designs.

a- Multiple layered.

In multiple layered tablets the first layer is formed by light compression of

granules containing the drug then a next layer of granules containing the drug is

compressed on the first layer.

b. – Compression coated

The first layer is prepared by light compression then removed and located in a

second press machine to feed granules with drug around the formed layer (on

the surface and edges) then compressed to form a coated layered tablet. The

inner tablet being the core and the outer portion being the shell.

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Application of using the multiple compressed tablets:

1- Separation of incompatible drug in separate layered tablet.

2- The delivery of therapeutic agents at different rates or to different sites within

G.I.T. from single tablet.

3- Production of coated tablets with an external layer that irritant to the stomach or

unstable in acidic PH.

3- Enteric coated tablets (E.C.T.)

They are tablets coated with a polymer that does not dissolve in acidic conditions

(stomach) but dissolve in alkaline conditions of small intestine (pH 7.4).The

polymers used for enteric coating inhibit the dissolution of the drug in the stomach

or protect the drug from degradation or protect the stomach mucosa from the

irritation caused by some drugs (anti-rheumatics).

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Polymers used for enteric coating:

1. Cellulose acetate phthalate (CAP) or cellulose acetate butyrate, the dissolution

of the polymer occurs in solution above pH 6.

2. Hydroxyl propyl methyl cellulose succinate (HPMCS): this polymer dissolves in

the intestinal secretions.

3. Methacrylic acid co- polymers (Eudragits): it is characterized by presence of a

wide range of functional groups which exhibit a range of solubilities. The available

Eudragits which resist dissolution in the stomach such as Eudragits L100 which

soluble in intestinal fluids from pH 5.5 and Eudragits S100 which is soluble in the

intestinal fluids from pH 7.

4- Sugar coated tablets (S.C.T.)

They are conventional tablets coated with a concentrated sugar solution to improve

the tablet appearance or to mask bitter taste of the drug. Now sugar-coated tablets

decreased in use for improved techniques of film coated tablets.

5- Film coated tablets (F.C.T.)

These are conventional tablets coated with a polymer or a mixture of polymers.

Film coated with polymers that dissolve in stomach (non enteric) to enable tablet

disintegration and dissolution such as:

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1. Hydroxyl propyl methyl cellulose (HPMC).

2. Hydroxyl propyl cellulose (HPC).

3. Eudragit E100.

If the film coating is employed to control the rate and duration of drug

release in certain region of G.I.T, the drug release occurs by diffusion

through the insoluble coating and subsequent partitioning into G.I.T fluids.

Examples of polymers used for this purpose:

1- Ethyl cellulose (EC): It is insoluble in aqueous solutions at all pH values.

2- Eudragit RS and RL: Are methacrylate co- polymers that are insoluble in water.

The RS differs from RL in the ratio of monomers.

6- Chewable tablets

These are tablets that chewed within the buccal cavity prior to swallowing and

applied mainly for:

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1. Administration to children and adults who have difficulty in swallowing

conventional tablets.

2. Antacid formulations in which the size of the tablet is related to particle size

within the stomach.

If the drug taste is not acceptable, it is not recommended to be manufactured in

chewable tablet.

7- Tablets for Solution (CTS)

Compressed tablets used for preparing solutions or imparting given characteristics

to solutions must be labeled to indicate they are not to be swallowed. Examples of

these tablets are Potassium Permanganate Tablets for Solution.

8-Effervescent tablets

They are tablets when added to aqueous solutions they will rapidly disintegrate

with effervescence producing solution or suspension of the drug, in aqueous

medium. The disintegration of the tablet is due to a chemical reaction occurs

between two components in the presence of water, with the evolution of CO2

which causes the disintegration. This type of tablets has the advantage of

producing a solution ready for absorption in G.I.T. The main disadvantage is the

need of a moisture impermeable package such as aluminum foil to inhibit the

interaction between the acid and sodium bicarbonate.

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8- Buccal and sublingual tablets:

Are dosage forms that held within oral cavity and slowly dissolve. The drug is

absorbed across the buccal mucosa to produce systemic effect. Buccal tablets are

placed between the cheek and the gingival while the sublingual tablets are placed

under the tongue. These tablets are employed to achieve rapid absorption and

avoiding first pass metabolism. Buccal and sublingual tablets should be formulated

to dissolve slowly in vivo and not disintegrate with retaining in the site of

application. It should not contain components that stimulate the production of

saliva.

9- Vaginal tablets

These are ovoid shaped tablets that are inserted into the vagina using a special

inserter. Following insertion retention and slow dissolution of the tablet occur

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release the therapeutic agent to provide local therapeutic effect, e.g. for the

treatment of bacterial or fungal infection. Vaginal tablets may also be used to

provide systemic absorption of the drug. It is important that dissolution and not

disintegration of the tablet occurs in vivo.

Manufacture of tablets

The manufacturing of tablets is depending mainly on the excipients and the

methods used

1- Excipients used in the manufacture of tablets

2- Methods used for the manufacture of tablets

1- Excipients used in the manufacture of tablets:

The following excipients are used in the manufacturing of the conventional tablets:

1- Diluents = fillers = bulking agents

2- Binders

3- Disintegrants

4- Lubricants

5- Glidants

6- Miscellaneous

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1- Diluents = fillers = bulking agents

They are employed in tablet formulation by any method to increase the mass of the

tablets that containing a low concentration of the drug rendering the process of

manufacture more reliable and reproducible. Diluents must exhibit good

compression proprieties and not expensive such as:

1. Anhydrous fructose

2. Lactose monohydrate

3. Spray dried lactose

4. Starch

5. Dibasic calcium phosphate

6. Microcrystalline cellulose (Avicel®)

7. Mannitol

Anhydrous lactose:

Is available in a range of particle sizes and used mainly as diluents in wet

granulation and dry granulation. It is a crystalline material.

Lactose monohydrate:

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It is available in a wide range of grades with different physical properties e.g.:

particle size and bulk density.

Spray dried lactose:

It is a mixture of crystalline α-lactose monohydrate (80- 90%) and 10-20%

amorphous lactose. It is prepared by spray drying a suspension of α-lactose

monohydrate. The specific use of spray dried lactose for the manufacture of tablets

by direct compression method.

Starch:

It is a polysaccharide composed of amylose and amylopectin used as diluent,

binder and disintegrants. Pregelatinized grade is available in which the granules of

starch physically and chemically modified to produce free flowing powder

(granular starch)

Dibasic calcium phosphate:

It is available as different hydrate forms with range of particle sizes. It is a basic

excipient and may react with acidic component in presence of moisture. It has an

excellent flow and compression property.

Microcrystalline cellulose ( MCC):

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It is crystalline powder prepared by controlled hydrolysis of cellulose. Different

grades are present that differ in physical and chemical properties such as density,

flow properties and particle size distribution. E.g.: Avicel PH- 101 (powder) and

Avicel PH- 102 (granular).

Mannitol:

It is a polyol used as diluents specially for chewable tablets due to its sweetness. It

has excellent flowability.

2. Binders (Adhesive)

Its role to bind powders together in the wet granulation process and to bind

granules together during compression

Example of commonly used binders:

1. Solution binders as starch, sucrose and gelatin.

2. Dry binders as microcrystalline cellulose and cross linked PVP.

Types of binders

1. Sugars

2. Polymeric materials

a) Natural polymers: Starches, gums, and gelatin

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b) Synthetic polymers: - Methyl, ethyl, hydroxypropyl cellulose and PVP.

Different binders used in tablet formulation:-

Name

Conc.

used

Solvent

Starch 5-10% Aqueous paste

Pregelatinized starch 5-10% Added dry to powder

Gelatin 2-10% Aqueous solution

Polyvinyl pyrrolidon 5-10% Aqueous alcoholic solution

Methyl cellulose 2-10% Aqueous solution

Sod. carboxy methyl cellulose 2-10% Aqueous solution

Ethyl cellulose 5-10%

Aqueous or hydro alcoholic

solution

Poly Vinyl alcohol 5-10% Aqueous solution

Different Ways to add a Binder:

1. Solution binder: As a dry powder which is mixed with the other ingredients

before wet granulation.

Mechanism of action:

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During the granulation procedure the binder dissolves partly or completely in the

liquid; as a solution which is used during wet agglomeration.

2. Dry binder

As a dry powder which is mixed with other ingredients before compaction.

Both binders are included in the formulation at low concentrations, 2 –10 %.

2- Disintegrants

They are employed to facilitate the breakdown of the tablet granules upon entry

into the stomach. The disintegrant is essential in hydrophobic tablets with high

compression force to enable disintegration within the pharmacopeia standards (15

minutes for conventional tablets).

Mechanisms of disintegration:

Disintegrant would swell in gastric fluids and exert sufficient mechanical pressure

within the tablet to cause it to break apart into small segments and thus hasten the

absorption by increasing surface area of particles.

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These disintegrants are mainly hydrophilic polymers.

Examples: sodium starch glycolate, croscarmellose sodium (a cross-linked sodium

carboxy methyl cellulose) (0.5 - 5%), crospovidone (2 – 5 %), and gelatinized

starch in 5 %.

4- Lubricants

Lubricants act at the interface between the face of the die and the surface of the

tablets to reduce the friction at the interface during ejection of the tablet from the

tablet press. Insufficient lubricant will lead to tablet defects, where high conc. of

lubricant will lead to reduced disintegration and dissolution. In addition, the time

of mixing of lubricant with granules as well as the particle size of the lubricant will

affect the performance of the lubricant. Over mixing may adversely affect tablet

disintegration and drug dissolution. The mixing of disintegrant and insoluble

lubricant together should be avoided for this should form a film of lubricant on the

disintegrant surface which reduce wettability of disintegrant.

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There are 2 main categories of lubricants:

1- Insoluble lubricants: They are added to the final mixing stage before tablet

compression. The efficacy of lubricant is enhanced if its area is increased (decrease

the particle size). Examples of insoluble lubricant material are:

1. Magnesium stearate (0.25 - 0.5 % w/w)

2. Stearic acid (1 – 3 % w/w).

2- Soluble lubricants:

They are used to overcome the bad effects of insoluble lubricant on the tablet

disintegration and drug dissolution, although the effect of insoluble lubricant

is superior than the soluble lubricants. Examples of soluble lubricant material are:

1. PEG 4000, 6000 or 8000 grades.

2. Sodium lauryl sulfate 1- 2 % w/w.

5- Glidants

They act to enhance the flow properties of powders within the hopper and into

tablet die in the tablet press. To achieve this effect the Glidants must be small in

particle size and to be arranged on the surface of the granules. Their concentration

must not exceed the recommended as it is hydrophobic and may affect the

disintegration of the tablet and the dissolution of the drug. Examples of glidants

are:

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1. Talc (0.5- 3 % w/w)

2. Colloidal silicon dioxide (0.1 - 0.5 % w/w)

6- Miscellaneous excipients

(1) Adsorbents

They are included to be adsorbed a liquid or semisolid component when

incorporated within the tablet formulation.

Examples: Magnesium oxide or carbonate and kaolin or bentonite.

(2) Sweetening agent / flavors

They are incorporated to control the taste and tablet acceptability especially

chewable tablets if the components have disagreeable taste.

Methods used for the manufacture of tablets

Tablets are commonly manufactured by one of the following processes:

1- Wet granulation: wet method

2- Dry granulation or slugging or roller compaction

3- Direct compression

Factors affect the choice of manufacture method:

1- Physical and chemical stability of the drug during manufacturing.

2- The availability of the necessary processing equipment.

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3- The cost of manufacturing process.

3- The excipients used to formulate the product

I. Wet granulation

Important steps involved in the wet granulation

1. The active ingredient and excipients are weighed and mixed.

2. The wet granulate is prepared by adding the liquid binder–adhesive to the

powder blend and mixing thoroughly.

3. Screening the damp mass through a mesh to form pellets or granules.

4. Drying the granules. A conventional tray-dryer or fluid bed dryer are most used.

5. After the granules are dried, they are passed through a screen of smaller size

than the one used for the wet mass to create granules of uniform size

Step 1: Mixing the therapeutic agent with the powdered excipients (without

lubricant). Using a mixer for a sufficient specified time and speed till become

homogenous.

Step 2: Wet granulation of the powder mix to make homogenous granules (0.2 - 4

mm diameter).

Description of wet granulation

1.To achieve cohesion between powders: we use a binder within the formulation

either in the solid state within the powder mix or dissolved in the binding fluid

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(water, isopropanol, or ethanol) the wetted mass is then passed into an oscillating

granulator which forces the wet mass through a metal screen under the action of an

oscillatory stress

2. Achieving wet granulation using high speed mixer/ granulator: This is more

recent as in this machine single operation is employed. e.g: high shear (speed)

mixer

3. Using fluidized bed drier for granulation and drying. This system of operation

includes 3 steps in one operation.

1. Mixing of powder,

2. Spraying the binder solution within mixing,

3. Applying hot air (controlled temperature) → the solvent will evaporate, and

the formed granules will be dried.

Advantages of granulation step in tablet manufacture

1. Prevention of segregation of powder component during manufacture process.

2. Enhancement of the flow properties from the tablet hopper to tablet dies in the

machine to prevent the variability in tablet weight.

3. Enhancement of the compaction properties due to the presence of binder on the

surface of granules leading to greater intergranule adhesive interactions.

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4. Lower incidence of dust production.

Excipients used in direct compression

To achieve the direct powder flow and compression properties, certain grades of

excipients are specially employed. These grades are prepared by specific methods

such as spray dried to achieve the correct flow and accurate distribution for all the

mix.

Examples of excipients used in direct compression

1) Diluent:

- Spray dried lactose: e.g.: lactopress, ludipress, pharmatose.

- Dicalcium phosphate encompress grade.

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- Mannitol granular or spray dried.

- Sorbitol.

- Microcrystalline cellulose: e.g.: Avicel pH102

2) Compression aid:

Such as Avicel pH 102

3) Disintegrants:

such as:

Pregelatinized starch, starch 1500.

Sodium starch glycolate e.g. Explotab.

Cross carmellose sodium e.g. Ac-di-sol , explocal.

Cross povidone: e.g. Kollidon CL

4) Lubricants and Glidants:

As used in wet granulations:

Lubricants such as magnesium stearate, stearic acid.

Glidants such as talc and colloidal silicon dioxide.

Advantages of direct compression

1. The process is less in cost (few steps).

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2. No need for liquid and no need for heat, hence the stability of the therapeutic

agent is ensured.

3. The lubrication is performed in the same vessel of powder mixing

Disadvantages of Direct Compression

1. Special excipients are required. Which more expensive.

2. The final tablet produced may be softer than that produce by wet

granulation.

3. If the therapeutic agent in the final formula is high the compression

properties of the final tablet may be affected.

4. In some cases, the physical properties of the drug may be unsuitable for

compression by their methods.

5. Direct compression is not used if colorant is required as this will produce

molted tablet.

Tablet Compression Machine: -

The basic unit of any tablet press consisting of two punches and a die which is

called a station. The die determines the diameter or shape of the tablet, the

punches. Upper and lower come together in the die that contains the tablet

formulation to form a tablet.

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Basic components of Tablet Presses:

1. Hopper for holding and feeding granules to be compressed.

2. Dies which define the size and shape of the tablet.

3. Punches for compressing the granules within the dies.

4. Cam tracks for guiding the movement of the punches.

5. Feed frame(s) for distributing the formulation to the dies.

Types of Tableting Press

1. Single Punch Machine

2. Multi-Station (Rotary) Machine

1. Single Punch Machine

A single-punch press possesses one die and one pair of punches. The powder

is held in a hopper which is connected to a hopper shoe located at the die

table. The hopper shoe moves to and from over the die, by either a rotational

or a transitional movement.

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Compression sequence in single punch machine: -

1) The upper punch is raised, and lower punch is dropped.

2) Feed shoe (hopper) has moved forward over die and granules fall into

die, then moved back. Compression sequence in single punch machine

3) Upper punch has come down compressing granules into tablet.

4) Upper punch has moved upwards, and lower punch has moved upwards

to eject tablet.

5) The cycle repeated.

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2. Multi-Station (Rotary) Machine

It is employed for the large-scale manufacture of tablets production up to 10000

tablet/minute. It is composed of series of upper and lower punches (up to 60 /

machine) housed in a circular die tablet which rotates in circular motion. The head

of the tablet machine that holds the upper punches, dies and lower punches in place

rotates.

Rotary Tablet Press Cycle. (Courtesy of Natoli.)

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Problems of tablet manufacture

1. Pitting

It is the production of pit marks on the surface of the tablet due to insufficient

lubricant at the tablet/ punch interface or may be due to rough surface of the

punches.

Improvement by increasing the concentration of the lubricant and polishing the

punch surface regularly to grievant such adhesion.

2- Capping

The partial or complete separation of the top or bottom of a tablet from

the main body.

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3- Lamination

The separation of a tablet into two or more distinct layers. Usually, these defects

are apparent immediately after compression, but may occur hours or even days

later. These due to entrapment of air among the granules. The air does not escape

during compression but afterward when the pressure is released. This problem can

be solved by ;

1-Fluffy materials may be identified by increasing the amount of binder or by

changing to a solvent system which increases the wetting of the granulation.

2-The granulation may be too dry, and a certain percentage of water is sometimes

essential to good compaction. The addition of a hygroscopic substance e.g.

sorbital, methylcellulose or polyethylene glycol 4000 can help to maintain the

proper moisture level.

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Tablet Coating: -

the tablet coating is needed for these reasons: -

1- To protect the drug from degradation in the stomach (enteric coating).

2- To prevent drug-induced irritation at a specific sit within G.I.T e.g. anti-

inflammatory drugs.

3- To provide controlled release of the drug through the G.I.T.

4- To target the drug release to a specific site in

5- To mask the Taste of the drug.

6- To improve the appearance of the tablet

Main steps of tablet coating

1- The tablets are placed within the coating apparatus and agitated.

2- The coating solution is sprayed on the surface of the tablets.

3- Warm air is passed over the tablets to facilitate removal of the solvent from the

adsorbed layer of coating solution on the tablet surface.

4- When the solvent is evaporated, the tablet will be coated with the solid

components of the coating solution.

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1- Coating Formation:

The coating materials (Polymers and sugar) + the coating solvent and other

excipients required to improve the formation. Such as colourants, opacifiers,

plasticizers.

2- Coating emulsions:

They are more recently developed, in which the polymer is dissolved in a volatile

organic phase with the plastic colourants and opacifiers; plasticizer is emulsified

within the external aqueous phase.

3- Coating process:

The initial stage in the coating process involves the deposition and subsequent

spreading of the atomized coating solution or emulsion. On the tablet surface, then

an initial film formation on the Surface of the table. As drying continuing. The

saturation solubility of the cooking mater in the Solvent is exceeded and the solid

coating is formed on the tablet surface.

Coating Problems

1. Picking and sticking.

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This occurs when the coating removes a piece of the tablet from the core. It is

caused due to over-wetting the tablets, under-drying, or poor tablet quality. This

can be treated by continuous addition of material to give uniform film.

2. Bridging.

A bridge is formed by peeling of the film over the writing symbols or logo which

is typically caused by improper application of the solution, poor design of the

tablet embossing, high coating viscosity, or improper

atomization pressure. This treated by using

1) wetting agent to decrease viscosity,

2) diluted solution of polymer

3) use effec2t9ive plasticizer

3. Capping.

This occurs when the tablet separates in laminar fashion. The problem occurs due

improper tablet compression, but it may not reveal itself until you start coating. Be

careful not to over- dry the tablets in the preheating stage, that can make the tablets

brittle and promote capping.

4. Twinning.

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This is the term for two tablets that stick together, and it’s a common problem with

capsule shaped tablets(oblong), you can solve this problem by balancing the pan

speed and spray rate.

5. Mottled color.

No uniform distribution of the color and its migration. This can happen when the

coating solution is improperly prepared, the actual spray rate differs from the target

rate, the tablet cores are cold, or the drying rate is out of specification.

6. Orange peel (roughness).

This refers to a coating texture that resembles the surface of an orange. It is usually

the result of high atomization pressure in combination with spray rates that are too

high. This can be treated by regulating the rate of drying.

Tablet Characteristics

Compressed tablets may be characterized or described by a number of

specifications. These include the diameter size, shape, thickness, weight, hardness,

disintegration time, and dissolution characteristics. The diameter and shape depend

on the die and the punches selected for the compression of the tablet. Generally,

tablets are discoid in shape, although they may be oval, oblong, round, cylindrical,

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or triangular. Their upper and lower surfaces may be flat, round, concave, or

convex to various degrees. The concave punches, used to prepare convex tablets,

are referred to as shallow, standard, and deep cup, depending on the degree of

concavity.

Quality control tests of Tablet

several quality control tests are performed to ensure that tablets produced meet the

requirements as specified in official compendium and conventional requirements

established by the industries over the years. These tests can be grouped into two

broad categories namely:

1) Pharmacopoeial or Official tests

2) Non-pharmacopoeial or Non-official tests

Pharmacopoeial or Official tests

They are called official tests because the test methods are described in official

compendia such as the British Pharmacopoeia, American Pharmacopoeias etc.

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They are standardized test procedures which have clearly stated limits under which

compressed tablets could be accepted. These tests include:

1- Content of Active Ingredient/ Absolute drug content test

2- Uniformity of Weight

3- Uniformity of Content

4- Disintegration time test

5- Dissolution test

Uniformity of Dosage Units

The term “uniformity of dosage unit” is defined as the degree of uniformity in the

amount of the drug substance in a tablet. The uniformity of dosage units can be

demonstrated by either one of two methods, Content Uniformity (CU) or Weight

Variation. CU testing was developed to ensure the content consistency of active

pharmaceutical ingredients (API) within a narrow range around the label claim in

dosage units. CU is related to efficacy, especially for low drug content where

manufacturing loss is the dominant problem, whereas, for potent and narrow

therapeutic indexed drugs, CU is also associated with safety. By default, all tablets

and capsules, as dosage units, are requested to pass the CU acceptance criteria, by

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direct individual analysis of each sampled unit, otherwise weight variation (WV)

procedure is to be applied, Theoretically, this new concept aims to assure dosage

units to have drug content not critically (within ±15%) deviating from the nominal

dose value.

Tablet Disintegration

It is recognized generally that the in vitro tablet disintegration test does not

necessarily bear a relationship to the in vivo action of a solid dosage form. To be

absorbed, a drug substance must be in solution, and the disintegration test is a

measure only of the time required under a given set of conditions for a group of

tablets to disintegrate into particles. Generally, this test is useful as a quality-

assurance tool for conventional dosage forms. In the present disintegration test, the

particles are those that pass through a 10-mesh screen. Regardless of the lack of

significance as to in vivo action of the tablets, the test provides a means of control

in ensuring that a given tablet formula is the same as regards disintegration from

one production batch to another. The disintegration test is used as a control for

tablets intended to be administered by mouth, except for tablets intended to be

chewed before being swallowed or tablets designed to release the drug substance

over a period of time. Exact specifications are given for the test apparatus, in as

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much as a change in the apparatus can cause a change in the results of the test. The

USP apparatus consists of a basket-rack assembly, a 1000-mL, low-form beaker,

138–160 mm in height and having an inside diameter of 97–115 mm for the

immersion fluid, a thermostatic arrangement for heating the fluid between 35°C

and 39°C, and a device for raising and lowering the basket in the immersion fluid

at a constant frequency rate between 29 and 32 cycles per minute through a

distance of not less than 53 mm and not more than 57 mm. The basket-rack

assembly moves vertically along its axis. There is no appreciable horizontal motion

or movement of the axis from the vertical.

USP Disintegration Tester. (Courtesy of SOTAX.)

Basket-Rack Assembly

The basket-rack assembly consists of six open-ended transparent tubes, each 77.5 ±

2.5 mm long and having an inside diameter of 20.7–23 mm and a wall 1.0– 2.8 mm

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thick; the tubes are held in a vertical position by two plates, each 88–92 mm in

diameter and 5–8.5 mm in thickness, with six holes, each 22–26 mm in diameter,

equidistant from the center of the plate and equally spaced from one another.

Attached to the under surface of the lower plate is a woven stainless steel wire

cloth, which has a plain square weave with 1.8- to 2.2-mm apertures and with a

wire diameter of 0.57-0.66 mm.

Dissolution Test

Currently, for most tablets, the monographs direct compliance with limits on

dissolution, rather than disintegration. Since drug absorption and physiological

availability depend on having the drug substance in the dissolved state, suitable

dissolution characteristics are important properties of a satisfactory tablet. Like the

disintegration test, the dissolution test for measuring the amount of time required

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for a given percentage of the drug substance in a tablet to go into solution under a

specified set of conditions is an in vitro test. the dissolution test does provide a

means of control in ensuring a given tablet formulation is the same as regards

dissolution as the batch of tablets shown, initially, to be clinically effective. It also

provides an in vitro control procedure to eliminate variations among production

batches

USP Dissolution Tester, Flow Through. (Courtesy of SOTAX)

Non-Pharmacopoeial or Non-Official Tests

These are tests that are performed on tablets, and which are not listed in official

compendia and concern a variety of quality attributes that need to be evaluated,

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such as the porosity of tablets, hardness or crushing strength test, friability test,

tensile strength determination, thickness test etc.

Some of these tests have no officially set limits for acceptance or rejection and thus

may vary from manufacturer to manufacturer and from formulation to formulation.

Crushing strength and friability appeared in the 2001 Edition of British

Pharmacopoeia (Appendix A324). There was however no definite set limits. The

two tests are, therefore, here considered under non-pharmacopoeial tests. These

tests include:

1- Hardness

2- Friability

3- Thickness

Tablet Hardness or Crushing Strength

The resistance of the tablet to chipping, abrasion, or breakage under conditions of

storage, transportation, and handling, before usage, depends on its hardness. In the

past, a rule of thumb described a tablet to be of proper hardness if it was firm

enough to break with a sharp snap, when it was held between the second and third

fingers and using the thumb as the fulcrum yet didn’t break when it fell on the

floor. For obvious reasons and control purposes, several attempts have been made

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to quantitate the degree of hardness. A small and portable hardness tester was

manufactured and introduced in the mid-1930s. The instrument measures the force

required to break the tablet, when the force generated by a coil spring is applied

diametrically to the tablet. The force is measured in kilograms. the most widely

used apparatuses to measure tablet hardness or crushing strength are the

electrically operated equipment, which eliminates the operator variability. Newer

equipment are also available with printers. Manufacturers

Electric Tablet Hardness Tester. (Courtesy of Erweka.)

Friability

A tablet property related to hardness is friability, and the measurement is made by

use of the Roche friabilator. Rather than a measure of the force required to crush a

tablet, the instrument is designed to evaluate the ability of the tablet to withstand

abrasion in packaging, handling, and shipping. A number of tablets are weighed

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110

and placed in the tumbling apparatus, where they are exposed to rolling and

repeated shocks, resulting from free-falls within the apparatus. After a given

number of rotations, the tablets are weighed, and the loss in weight indicates the

ability of the tablets to withstand this type of wear. The friability test is now

included in the USP.

Tablet Friability Testers. (Courtesy of Erweka.)

Tablet Thickness

The thickness of the tablet from production-run to production run is controlled

carefully. Thickness can vary with no change in weight, due to difference in the

density of the granulation and the pressure applied to the tablets, as well as the

speed of tablet compression. Not only is the tablet thickness important in

reproducing tablets identical in appearance, but also to ensure that every

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production lot will be usable with selected packaging components. If the tablets are

thicker than specified, a given number no may longer be contained in the volume

of a given size bottle. Tablet thickness also becomes an important characteristic in

counting tablets using filling equipment. Some filling equipment uses the uniform

thickness of the tablets as a counting mechanism. Tablet thickness is determined

with a caliper or thickness gauge that measures the thickness in millimeters. Plus,

or minus 5% may be allowed, depending on the Standard Operating Procedures

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113

Capsules

Definition: capsules are solid dosage forms in which the medication

contained within gelatin shells. The medication may be a powder, a liquid or

a semisolid mass. Capsules are usually intended to be administered orally by

swallowing them whole.

Advantages

1) Neat and elegant in appearance.

2) Suitable for substances having bitter taste and unpleasant odor.

3) The ready solubility of gelatin at gastric pH provides rapid release of

medication in the stomach.

4) As produced in large quantities it is economic, attractive and available

in wide range of colors.

5) Minimum excipients required.

6) Little pressure required to compact the material.

7) Unit dosage form.

8) Easy to store and transport.

Disadvantages

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114

1) Capsules are not suitable containers for liquids that dissolve gelatin,

such as aqueous or hydroalcoholic solutions.

2) Very soluble salts, such as bromides or iodides should not be

dispensed in capsules, as the rapid release of such materials may cause

gastric irritation.

Types of capsules

1) Hard gelatin capsules

2) Soft gelatin capsules

Basic components of capsules

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115

Gelatin

It is the major component of the capsule. Gelatin is a product obtained by

partial hydrolysis of collagen acquired from the skin, white connective

tissue, and bones of animals. Gelatin is a protein which is soluble in warm

(or hot) water, but insoluble in cold water. At low temperatures, gelatin

dissolved in water becomes a gel (which is insoluble in water). Gelatin

capsules become dissolved in warm gastric fluid and release the contents.

There are two types of gelatin:

TYPE A

Produced by acid hydrolysis of animal skins, mainly from pork skin.

TYPE B

Produced by basic hydrolysis of bovine bones.

Colorants

Colorants may be added to the gelatin solution to prepare capsule shells with

a variety of colors. Both colored and opaque capsules make a

pharmaceutical product distinctive. By combining the various capsule parts

with different colors, distinctive capsules can be prepared. This is important

for those who have to take more than one type of drugs in the capsule dosage

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116

form. Different drugs in different capsules may be easily distinguished by

their colors of the capsules.

There are two types:

1) Water soluble dyes – e.g. erythrosine

2) Pigments – e.g. iron oxides, titanium dioxide (make the capsule

opaque to provide protection against light)

Process aids

Process aids are materials that assist in the manufacturing process.

Lubricant: added to the active compound to facilitate the flow of the

drug-fill into the encapsulating machinery. The use of lubricant is

especially important when an automatic capsule filling machine is

utilized ex: Magnesium stearate (frequently less than 1%). The water-

proofing property of the insoluble magnesium stearate may cause a

dissolution problem in the gastrointestinal fluid. The delayed

dissolution and subsequent delayed absorption may result in totally

different pharmacokinetic profiles than the desired

Surfactant: enable the polymer solution to take up the shape of the

mould better. Ex: sodium lauryl sulphate. The USNF describes the use

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117

of gelatin containing not more than 0.15% w/w of sodium lauryl

sulphate for use in hard gelatin capsule manufacture

Flavoring agent: materials that help to improve the patient

acceptability of the product by enhancing its odor.

Preservatives: they may be used or not to prevent the microbial

growth.

Capsule Size Capsule shells are manufactured in various sizes, lengths,

diameters, and capacities. For human use, capsules ranging in size from 000

(the largest) to 5 (the smallest) are commercially available. Larger capsules

are used in veterinary applications.

Fig: Capsule size

Hard gelatin capsules

The majority of capsule products are made of hard gelatin capsules. Hard

gelatin capsules are made of two pieces in the form of cylinders: the longer

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118

piece “body” and the shorter piece “cap” shorter cap. The cap fits snugly

over the open end of the capsule body.

Hard gelatin capsules are typically filled with dry solids (powders, granules,

pellets, tablets) and semisolids. Fixed oils and other liquids that do not

dissolve gelatin may be filled into hard gelatin capsules with a pipette or

calibrated dropper, then capsules are sealed by moisturizing the lower part of

the caps with water.

Limitations in properties of materials for filling into capsules:

Must not react with gelatin e.g. formaldehyde (make the capsule

insoluble).

Must not contain a high level of free moisture (can be absorbed by

gelatin causing it to soften).

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Fig: Hard gelatin capsule

Manufacture:

1) The manufacturing machines consist of two parts, which are mirror

images of each other: on one half the capsule cap is made and on the

other the capsule body. The moulds 'pins', are made of stainless steel

and are mounted in sets on metal strips, called 'bars'.

2) There are approximately 40000 mould pins per machine.

3) The prepared gelatin solution is then transferred to a heated holding

hopper on the manufacturing machine.

4) The level of solution is maintained automatically by a feed from the

holding hopper.

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120

5) By dipping sets of moulds, which are at room temperature, 22°C, into

this solution → capsules are formed.

6) A film is formed on the surface of each mould by gelling.

7) The moulds are slowly withdrawn from the solution and then rotated

during their transfer to the upper level of the machine, in order to form

a film of uniform thickness.

8) Groups of 'pin bars' are then passed through a series of drying ovens,

in which large volumes of controlled humidity air are blown over

them.

9) The dried films are removed from the moulds, cut to the correct

length, the two parts joined together and the complete capsule

delivered from the machine.

10) The mould pins are then cleaned and lubricated for the start of

the next cycle.

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121

Fig: Capsule manufacture

Methods of filling capsules

(1) Manual filling

With a spatula is formed into a cake having a depth of one fourth the length

of the capsule body. The powder to be encapsulated is placed on a sheet of

clean paper or a glass or porcelain plate. The cap is removed and the empty

capsule body is held between thumb and forefinger and repeatedly punched

downward until it is full. The cap is replaced and the filled capsule is

weighed using an empty capsule of the same size as a zeroing weight.

(2) Industrial filling

The industry uses semi-automatic and fully automatic equipment for the

large-scale filling of capsules. The semi-automatic machine is capable of

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122

filling all capsule sizes from 000 through 5 and attains its maximum rated

capacity of 15,000 capsules per hour.

Capsules are delivered into the perforated capsule filling ring. The ring is

rotated on a turntable, and a vacuum pulls the bodies into the lower half of

the ring, leaving the caps in the upper half of the ring.

The top & bottom halves of the filling ring are separated manually, and the

cap half of the ring is set aside. The body half of the ring is then moved to

another turntable where it is rotated mechanically under a powder hopper.

The hopper contains an auger which feeds the powder into the bodies. When

the capsule bodies are filled, the cap and body rings are rejoined.

Soft gelatin capsules

Soft gelatin (also called softgel or soft elastic) capsules consist of one-piece

hermetically-sealed soft shells.

Soft gelatin capsules differ from hard gelatin capsule in the following:

1) They are prepared by adding a plasticizer, such as glycerin or

polyhydric alcohol (e.g., sorbitol), to gelatin. The plasticizer makes

gelatin elastic.

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123

2) Soft gelatin capsules come in various shapes such as spherical,

elliptical, oblong, and special tube shapes.

3) Soft gelatin capsules contain more moisture than the hard capsules.

Since gelatin is subject to microbic decomposition when it becomes

moist, soft gelatin capsules must be prepared with preservatives to

prevent the growth of fungi.

4) Gelatin used for making soft capsules is usually of bone and skin

origin

5) They can contain non-aqueous liquids, suspensions, pasty materials,

or dry powders.

Advantages of Soft Gelatin Capsules

1) Ease of swallowing

2) Dosage accuracy/uniformity: Precise fill volume of liquid fill unit

delivers a greater degree of accuracy and consistency from capsule-to-

capsule and lot-to-lot.

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124

3) Consistent manufacturing requirements: More accurate compounding,

blending, and dispensing of liquid fill facilitates manufacturing.

Liquid blends are more homogeneous. They are especially important

to contain volatile drug substances or drug materials susceptible to

deterioration in the presence of air.

4) Increase in bioavailability, absorption and bioavailability can be

enhanced by formulating compounds in solution including solubilizers

and absorption enhancers, if necessary. Water-insoluble drugs may be

formulated in a softgel.

5) Enhanced stability and security: The tight hermetical sealing protects

fill from air and environmental contamination.

6) Gelatin shell can be formulated to block out ultraviolet light.

7) Pliable shell: soft gel shell allows for custom shapes and sizes ap-

propriate for oral, topical, chewable and suppository delivery.

8) Portability: Encapsulated liquid dosage formulations become highly

portable for consumers/patients

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Fig: Schematic drawing of a rotary-die soft gelatin capsule filler

Quality Control Tests For finished Pharmaceutical Capsules

1- Uniformity of weight and content of active ingredient

The control of uniformity of weight may be generally presumed to be a

sufficient controlling over the uniformity of actual drug content in relatively

little diluent or excipient present. In the case of more potent, low-dose drugs,

less than 2mg or less that 2% by weight of the total weight of the capsule

fill, the control of uniformity of weight does not offer sufficient assurance of

the uniformity of drug content, since adequate blending may not have been

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126

achieved. In this case a content uniformity test should be performed as stated

in the official compendia.

2- Dissolution:

Disintegration of a tablet or dissolution of a capsule shell does not imply

complete dissolution of the active ingredient. Since the dissolution of a drug

is considered to be an essential step in the absorption process, the

availability of a drug for absorption from a dosage form largely depends on

the drugs dissolving in gastro-intestinal fluid. Often dissolution is

the rate-limiting step (i.e., the slowest step) in the over-all absorption

process.Various factors, including the physicochemical properties of the

drug, how it is formulated, and how it is processed can significantly affect

drug availability.

The dissolution test is carried out using the dissolution apparatus official in

both the U.S.P. and N.F. In general, the capsule or tablet sample is placed in

a basket formed from 40-mesh stainless steel fabric. A stirrer shaft is

attached to the basket, and the basket is immersed in the dissolution medium

and caused to rotate at a specified speed. The dissolution medium (900 ml,

unless otherwise specified in the individual monograph) is held in a

covered 1000 ml. Vessel made of glass or other transparent material. The lid

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127

has four holes: two to accommodate the stirrer shaft and a thermometer, two

for sampling and fluids exchange. The dissolution medium is maintained at

37° ± 0.5 by means of a suitable constant-temperature water bath.

The stirrer speed and type of dissolution medium are specified in the

individual monograph.

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129

Suppositories

Suppositories are solid dosage forms intended for insertion into body orifices where

they melt, soften, or dissolve and exert local or systemic effects. The derivation of

the word suppository is from the Latin supponere, meaning “to place under,” as

derived from sub (under) and ponere (to place). Thus, suppositories are meant both

linguistically and therapeutically to be placed under the body, as into the rectum.

Ideal suppository should have the following characters:

1) The shape and size of a suppository must be such that it can be easily inserted

into the intended orifice without causing undue distension.

2) Once the suppository inserted, it must be retained for the appropriate period.

Then it has to melt, soften or dissolve.

Application of suppositories

Suppositories are commonly used rectally and vaginally and occasionally

urethrally. They have various shapes and weights.

Rectal suppositories Rectal suppositories are usually about 32 mm (1.5 in.) long,

are cylindrical, and have one or both ends tapered. Some rectal suppositories are

shaped like a bullet, a torpedo, or the little finger. Depending on the density of the

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130

base and the medicaments in the suppository, the weight may vary. Adult rectal

suppositories weigh about 2 g when cocoa butter is employed as the base. Rectal

suppositories for use by infants and children are about half the weight and size of

the adult suppositories and assume a more pencil like shape.

Vaginal suppositories

Also called pessaries, are usually globular, oviform, or cone-shaped and weigh

about 5 g when cocoa butter is the base. However, depending on the base and the

manufacturer’s product, the weights of vaginal suppositories may vary widely.

Certain vaginal suppositories, particularly the inserts, or tablets prepared by

compression, may be inserted high in the tract with the aid of an appliance.

Urethral suppositories

Also called bougies, are slender, pencil-shaped suppositories intended for insertion

into the male or female urethra. Male urethral suppositories may be 3 to 6 mm in

diameter and approximately 140 mm long, although this may vary. When cocoa

butter is employed as the base, these suppositories weigh about 4 g. Female urethral

suppositories are about half the length and weight of the male urethral suppository.

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131

Suppositories may be indented either for local or systemic action:

Local action

Once inserted, the suppository base melts, softens, or dissolves, distributing its

medicaments to the tissues of the region. These medicaments may be intended for

retention within the cavity for local effects, or they may be intended to be absorbed

for systemic effects. Rectal suppositories intended for local action are most

frequently used to relieve constipation or the pain, irritation, itching, and

inflammation associated with hemorrhoids or other anorectal conditions.

Antihemorrhoidal suppositories frequently contain a number of components,

including local anesthetics, vasoconstrictors, astringents, analgesics, soothing

emollients, and protective agents. A popular laxative, glycerin suppositories promote

laxation by local irritation of the mucous membranes, probably by the dehydrating

effect of the glycerin on those membranes. Vaginal suppositories or inserts intended

for local effects are employed mainly as contraceptives, antiseptics in feminine

hygiene, and as specific agents to combat an invading pathogen. Urethral

suppositories may be antibacterial or a local anesthetic preparative for a urethral

examination.

Systemic action

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For systemic effects, the mucous membranes of the rectum and vagina permit the

absorption of many soluble drugs. Although the rectum is used frequently as the site

for the systemic absorption of drugs, the vagina is not as frequently used for this

purpose. Rectal administration of drugs for systemic action has the advantages over

oral therapy that is drugs destroyed or inactivated by the pH or enzymatic activity of

the stomach or intestines need not be exposed.

Factors affecting drug absorption from rectal suppositories

The dose of a drug administered rectally may be greater than or less than the dose of

the same drug given orally, depending on such factors as the constitution of the

patient, the physicochemical nature of the drug and its ability to traverse the

physiologic barriers to absorption, and the nature of the suppository vehicle and its

capacity to release the drug and make it available for absorption.

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(A) Physiologic factors

The human rectum is approximately 15 to 20 cm long. When empty of fecal

material, the rectum contains only 2 to 3 mL of inert mucous fluid. In the resting

state, the rectum is not motile; there are no villi or microvilli on the rectal mucosa.

However, there is abundant vascularization of the submucosal region of the rectum

wall with blood and lymphatic vessels.

Among the physiologic factors that affect drug absorption from the rectum are

the colonic contents, circulation route, and the pH and lack of buffering capacity of

the rectal fluids.

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1) Colonic Content

When systemic effects are desired, greater absorption may be expected from a

rectum that is void than from one that is filled with fecal matter. A drug will

obviously have greater opportunity to make contact with the absorbing surface of the

rectum and colon in an empty rectum. Therefore, when high effect is desirable, an

evacuant enema may be administered and allowed to act before the administration of

a suppository of a drug to be absorbed. Other conditions, such as diarrhea, colonic

obstruction due to tumor, and tissue dehydration can all influence the rate and degree

of drug absorption from the rectum.

2) Circulation Route

Drugs absorbed rectally, unlike those absorbed after oral administration, bypass the

portal circulation during their first pass into the general circulation, thereby enabling

drugs otherwise destroyed in the liver to exert systemic effects. The lower

hemorrhoidal veins surrounding the colon receive the absorbed drug and initiate its

circulation throughout the body, bypassing the liver. Lymphatic circulation also

assists in the absorption of rectally administered drugs.

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3) pH and Lack of Buffering Capacity of the Rectal Fluids

Because rectal fluids are essentially neutral in pH and have no effective buffer

capacity, the form in which the drug is administered will not generally be chemically

changed by the environment.

The principal method of drug absorption from the rectum is by passive diffusion. So

a drug that remains mostly in unionized state will be absorbed more readily.

Generally weakly basic and weakly acidic drugs remains in unionized state in the pH

of rectum (6.8) and hence, absorbed readily than the stronger base or acids

(B) Physicochemical factors of the drug and suppository base

Physicochemical factors include such properties as the relative solubility of the drug

in lipid and in water and the particle size of a dispersed drug. Physicochemical

factors of the base include its ability to melt, soften, or dissolve at body temperature,

its ability to release the drug substance, and its hydrophilic or hydrophobic character.

1) Lipid–Water Solubility

The lipid–water partition coefficient of a drug is an important consideration in the

selection of the suppository base and in anticipating drug release from that base.

Water-insoluble bases release the hydrophilic drug in a higher rate than the

hydrophilic one as lipophilic drug that is distributed in a fatty suppository base has

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fewer tendencies to escape to the surrounding aqueous fluids than a hydrophilic

substance in a fatty base. Water soluble bases, for example polyethylene glycols,

that dissolve in the rectal fluids release for absorption both water-soluble and oil-

soluble drugs.

Naturally, the more drug a base contains, the more drug will be available for

absorption up to certain limit depending on the drug above which increase in drug

concentration has no effect on drug absorption.

2) Particle Size

For un-dissolved drugs in a suppository, the size of the drug particle will influence

its rate of dissolution and its availability for absorption. As indicated, the smaller the

particle, the greater the surface area, the more readily the dissolution of the particle

and the greater the chance for rapid absorption.

3) Nature of the Base

As indicated earlier, the base must be capable of melting, softening, or dissolving to

release its drug for absorption. If the base interacts with the drug to inhibit its

release, drug absorption will be impaired or even prevented. Also, if the base

irritates the mucous membranes of the rectum, it may initiate a colonic response and

bowel movement, eliminating the process of complete drug release and absorption.

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137

Because of the possibility of chemical and/or physical interactions between the

medicinal agent and the suppository base, which may affect the stability and/or

bioavailability of the drug, the absence of any drug interaction between the two

agents should be ascertained before or during formulation.

Change the type of the base may be useful in preparing long-acting or slow-

release suppositories. Morphine sulfate in slow-release suppositories is prepared by

compounding pharmacists. The base includes a material such as alginic acid, which

will prolong the release of the drug over several hours.

Suppository bases

Properties of ideal suppository base

1) It should melt at rectal temperature (360) or dissolve or disperse in body fluid.

2) Release medicaments easily.

3) Shape should remain intact while handling.

4) Non-toxic and non-irritant to sensitive and inflammed mucous membrane.

5) It should be stable on storage i.e. it does not change color, odor, or drug

release pattern.

6) Compatible with broad variety of drug and adjuvants.

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7) It should shrink so that it comes out easily from the mould without the use of

any lubricants.

For fatty bases the following additional specifications are required:

8) “Acid value” is below 0.2.

9) “Saponification value” ranges from 200 to 245.

10) “Iodine value” is less than 7.

11) The interval point and solidification point is small.

Classification and characteristics of suppository bases

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139

1) Fatty bases

1.1. Theobroma oil (Cocoa butter)

Source

Fat from the seeds of Theobroma cacao (chocolate beans) obtained

either by expressing the oil from the seeds or by solvent extraction

Chemical

nature

Chemically, it is a mixture of triglycerides of saturated and

unsaturated fatty acids, primarily stearic, palmitic, oleic, lauric, and

linoleic acid.

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140

Physical

state

Solid at room temperature but melts at body temperature with a

melting point of 31° to 34°C.

Appearance It is a mellow, yellowish solid with a mild odor and bland taste.

Solubility

It is insoluble in water, slightly soluble in alcohol, and soluble in

boiling absolute alcohol

Advantages

1) Bland and nonirritating to sensitive membrane tissues.

2) Ready liquefaction on warming and rapid setting on cooling.

3) Miscibility with many ingredients.

4) Cocoa butter is available in grated form. This eliminates one

time-consuming aspect of compounding suppositories.

5) It is also an excellent emollient and is used alone or in topical

skin products for this property.

Disadvantag

es

1) Low melting point, so cocoa butter suppositories must be

stored in the refrigerator (temperature not exceed 25°C)

2) They may melt at room temperature, or the suppositories may

liquefy when handled by the patient during insertion.

3) Existing in several polymorphic forms that have even lower

melting points: 18°, 24°, and 28°C to 31°C

4) As with all fatty bases, if cocoa butter is over-heated it may

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141

produce, on cooling, unstable crystals, which melt at about

150C, these unstable forms, if set by cooling, may re-melt in

the room temperature or by warmth of the patient’s hands.

5) This lowering of the solidification point can also lead to

sedimentation of suspended solids.

6) Suppositories may give poor and erratic release of some drugs.

7) Because cacoa butter does not contract enough on cooling to

loosen the suppositories in the mould, sticking may occur,

particularly if the mould is worm. This is prevented by

lubricating the mould before use.

8) Slow deterioration during storage due to oxidation of the

unsaturated glycerides

9) Poor water absorbing capacity. This can be improved by the

addition of emulsifying agents.

10) Sometimes melted base escapes from the rectum or

vagina. This is most troublesome with pessaries because of

their larger size, and therefore, these are rarely made with

theobroma oil.

11) Relatively high cost.

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142

1.2. Synthetic fats (Emulsifying bases)

Source substitute of theobroma oil

Chemical

nature

number of hydrogenated oils, e.g. hydrogenated edible oil, arachis oil,

coconut oil, palm kernel oil which are modified by esterification,

hydrogenation, and fractionation to obtain products of varying

composition and melting temperatures

this type of base is composed primarily of mixtures of triglyceride

esters of saturated fatty acids in the C-12 to C-18 range

Physical

state

Witepsol

Witepsol is a whitish, waxy, brittle solid that melts to a clear to

yellowish liquid; it is nearly odorless. It contains emulsifying agents

and will absorb a small amount of water.

Although suppositories made with this base solidify rapidly and

should contract to release easily from the mold, there are reports of

problems with suppositories breaking into pieces when being

removed from the suppository mold.

Appearance

Solubility

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143

Advantages

1. Over heating does not alter the physical characteristics.

2. They solidify rapidly.

3. They have good resistance to oxidation and getting rancid because

their unsaturated fatty acids have been reduced.

4. No mould lubricant is required and no mould sticking because

they contract significantly on cooling.

5. They produce colorless, odourless and elegant suppositories.

6. They can absorb fairly large amount of aqueous liquids with good

emulsifying properties.

Disadvantag

es

1. They should not be cooled in refrigerator because they become

brittle if cooled quickly. Certain additives e.g. 0.05 %

polysorbate80, help to correct this fault.

2. They are more fluid than theobroma oil when melted and at this

stage sedimentation rate is greater. Thickeners such as magnesium

stearate , bentonite and colloidal silicon dioxide, may be added to

reduce this.

2) Glycerin-Gelatin base

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144

Source Mixture of glycerol and water made into a stiff jelly by adding gelatin

Chemical

nature

Two types of gelatin:

Type-A or Pharmagel-A which is made by acid hydrolysis (has

isoelectric point between 7 to 9), used for acidic drugs.

Type-B or Pharmagel-B which is prepared by alkaline hydrolysis

(having an isoelectric point between 4.7 to 5), used for alkaline drugs.

Physical

state

It is used for the preparation of jellies, suppositories and pessaries.

The stiffness of the mass depends upon the proportion of gelatin used

which is adjusted according to its use. Appearance

Solubility

The base being hydrophilic in nature slowly dissolves in the aqueous

secretions and provide a slow continuous release of medicament.

Advantages

1. Glycerogelatin base is well suited for suppositories containing

belladonna extract, boric acid, chloral hydrate, bromides,

iodides, iodoform, opium, etc

2. They do not melt but dissolve slowly in the mucous secretions

of the vagina, so they are recommended for sustained release of

local antimicrobial agents

3. Glycerinated gelatin suppositories should be moistened before

insertion.

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145

4. Glycerinated gelatin suppositories are hygroscopic, so they

must be dispensed in tight containers.

5. They are reported to support mold or bacterial growth, so they

should be stored in the refrigerator and should contain a

preservative

Disadvantag

es

1) Glycerol has laxative action.

2) They are more difficult to prepare and handle.

3) Their solution time depends on the content and quality of the

gelatin and the age of the base.

4) They are hygroscope, hence must be carefully stored.

5) Gelatin is incompatible with drugs those precipitate with the

protein e.g. tannic acid, ferric chloride, gallic acid, etc.

3. Water soluble and water miscible base

3.1 Polyethylene glycol bases / Macrogol bases (Carbowaxes)

Source Polyethylene glycols are polymers of ethylene oxide and water,

prepared to Chemical

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146

nature various chain lengths, molecular weights, and physical states

They are available in a number of molecular weight ranges and melting

ranges.

The numerical designations refer to the average molecular weights of

each of the polymers.

Physical

state

Polyethylene glycols having average molecular

weights of 300, 400, and 600 are clear, colorless liquids. Those having

average molecular weights of greater than 1000 are wax-like, white

solids with the hardness increasing with an increase in the molecular

weight.

Appearanc

e

Solubility

PEG is soluble in water, methanol, ethanol, acetonitrile, benzene,

and dichloromethane, and is insoluble in diethyl ether and hexane

Advantage

s

The ratios of the low to the high molecular weight individual PEGs can

be altered to prepare a base with a specific melting point.

The mixtures generally have a melting point above 420C, hence, does

not require cool storage and they are satisfactory for use in hot climate.

Because of the high melting point they do not melt in the body cavity,

rather they gradually dissolve and disperse, releasing the drug slowly.

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147

They do not stick to the wall of the mould since they contract

significantly on cooling.

Disadvanta

ges

1. Irritating to body cavity tissues

2. Interact with polystyrene, the plastic often used for

prescription vials

Manufacturing of suppositories

Moulds

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148

Fig: Suppository moulds

The suppository and pessary moulds are made of metals and have four, six or twelve

cavities. By removing a screw, they can be opened longitudinally for lubrication,

extraction of the suppositories and cleaning.

The interior of the mould should never be scrapped or rubbed with abrasive. For

cleaning they are immersed in hot water containing detergent, wiped gently with soft

cloth and rinsed thoroughly.

The nominal capacity of a mould varies with the base selected. Each mould should

be calibrated before use by preparing a set of suppositories or pessaries using the

base alone, weighing the products and taking the mean weight as the true capacity.

This procedure is repeated for each base.

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149

Displacement value

It is the quantity of the drug that displaces one part of the base. The volume of a

suppository from a particular mould is uniform but its weight will differ with the

density of the base. e.g. Zinc oxide, D = 5.

Lubrication of the mould

If the cavities are imperfect, i.e. poorly polished or scratched, it may be difficult to

remove the suppositories without damaging their surfaces. So lubrication of the

moulds is necessary. The type of the used lubricant differs according to the type of

the base as such the following schematic explanation:

Suppositories

150

Methods of suppositories preparation

1 2 3 4

Hand molding

[Cold Hand

Shaping]

Compression

molding

Pour molding

(Fusion method)

Automatic

molding

machine

1. Hand molding [Cold Hand Shaping]

Suppositories

151

Fig: Hand molding of suppositories

Drug is triturated in a mortar into fine powder.

Cocoa butter is grated into small particles.

Drug is mixed with small portion of cocoa butter in a mortar.

One drop fixed vegetable oil is added to give plasticity to the mass.

Remainder of the cocoa butter is added by geometric dilution (i.e. by adding the

same amount of base as is already in the mortar), triturated with pressure. Heat

generated by trituration results in a plastic mass, which is cohesive and ready to

roll.

The mass is scrapped from the mortar with a spatula and rolled into a ball.

An ointment tile is taken, dusted lightly with starch powder, ball is placed on

it, rolled with a flat faced spatula to form a cylinder. The cylinder is cut into

desired number of pieces with a sharp blade.

One end of a suppository is held firmly with a finger and the other end is

tapered with the spatula to give the shape of suppository.

2. Compression molding

Suppositories

152

Fig: Compression mould

In this case an instrument known as compression mould is used.

Drug is powdered and mixed with grated cocoa butter.

The mixture is filled into a chilled cylinder. The mixture is pressed within

the cylinder by a piston until a pressure is felt.

Then the suppositories are expelled from the cylinder.

3. Pour molding (Fusion method)

Suppositories

153

Fig: Fusion molding of suppositories

This is the main method of preparing suppositories.

Drug is powdered in a mortar.

Carefully grated cocoa butter is taken into a beaker and heated in a water

bath. When 2/3rd

portion is melted the beaker is taken out of the heat

source. The rest of the mass is melted by stirring with a glass rod. [If cocoa

butter is heated to clear liquid then unstable, and crystals will form and the

suppositories will remain in melted state at room temperature].

Drug is added into the beaker and stirred thoroughly to mix with the

“creamy” base.

The “creamy” melted base is then poured into previously lubricated mould.

The mould is allowed to congeal, then placed in the refrigerator for 30

minutes to harden.

Suppositories

154

Mould is taken out from the refrigerator and surface is trimmed off. The

mould is opened and the suppositories are expelled out of the mould by

gentle pressure with the finger.

4. Automatic molding machine

Fig: Automatic molding machine

Two types of molding machines are available: (a) rotary molding machine and (b)

straight-line molding machine

Manufacturing cycles in rotary molding machine:

Prepared mass is filled in a into a filling hopper where it is continuously

mixed and maintained at constant temperature.

Suppositories

155

The suppository molds are lubricated by brushing or spraying lubricant

solution.

The molten mass is filled in the molds to a slight excess.

The mass is cooled to solidify and the excess material is scrapped off and

collected for re-use.

In the ejecting section the mold is opened and the suppositories are pushed out

by steel rods.

The mold is closed, and then moved to the first step of the cycle.

The output of a typical rotary machine ranges from 3500 to 6000 suppositories

an hour.

Manufacturing cycles in straight-line molding machine:

Here the cycle is similar to rotary molding machine but the individual molds are

carried on a track through a cooling tunnel, where scrape-off and ejection occur.

Packaging of molded suppositories

The suppositories should be over-wrapped, or they must be placed in a container in

such a way that they do not touch each other. Suppositories in contact with one

another may fuse with one another or with the container at room temperature.

Suppositories are usually over-wrapped in aluminium foils, paper strip or plastic

Suppositories

156

strips. The individually wrapped suppositories are packaged in slide, folding, or set-

up boxes so that if the suppository melts at higher storage temperature their shapes

are retained which can be used just by chilling again.

In plastic wrapping the plastic is thermoformed into the shape of mould. The molten

mass is injected through the top end and tops is cooled and sealed.

In aluminium foil method two aluminium foils are embossed and sealed to give the

shape of a mold and then the mass is injected at the top and then the top is cooled

and sealed.

Specific problems in formulating suppositories

1) Water in suppositories

Water is used as a solvent to incorporate a water-soluble substance in the

suppository base. Incorporating water should be avoided for the following

reasons.

(a) Water accelerates the oxidation of fats.

(b) If the water evaporates the dissolved substances crystallize out.

(c) In presence of water, reactions between various ingredients of

suppositories may occur.

Suppositories

157

(d) The water may be contaminated with bacteria or fungus.

2) Hygroscopicity

Glycerinated gelatin suppositories lose moisture in dry climates and absorbs

moisture in high humidity. Polyethylene glycol bases are also hygroscopic.

3) Incompatibilities

Poyethylene glycol bases are incompatible with silver salts, tannic acid,

aminopyrine, quinine, ichthammol, aspirin, benzocaine, iodochlorohydroxyquin, and

sulfonamides.

Many chemicals have a tendency to crystallize out of PEG e.g. sodium barbital,

salicylic acid and camphor.

4) Viscosity

Viscosity of melted base is low in cocoa butter and high in PEG and glycerinated

gelatin. Low viscosity base when melted the suspended particles may sediment very

quickly producing nonuniform distribution of drugs.

To solve this problem:

Suppositories

158

(a) The base should be melted at the minimum temperature required to maintain

the fluidity of the base.

(b) The base is constantly stirred in such a way that the particles cannot settle and

no air is entrapped in the suppository.

(c) A base with a narrow melting range closer to rectal temperature is used.

(d) Inclusion of approximately 2% aluminium monostearate increase the viscosity

of the fatty base and also helps in homogeneous suspension of particles.

(e) Cetyl, stearyl, myristyl alcohol or stearic acid are added to improve the

consistency of suppositories.

5) Brittleness

Cocoa butter base is not brittle but synthetic fat bases with high degree of

hydrogenetation and high stearate containing bases are brittle.

Brittle suppositories produce trouble during manufacture, handling, packaging, and

during use.brittlness occurs due to rapid chilling (shock cooling) of the melted bases

in an extremely cold mold.

To solve this problem:

Suppositories

159

(a) The temperature difference between the melted base and mold should be as small

as possible.

(b) Addition of small amount of Tween80, castor oil, glycerin or propylene glycol

imparts plasticity to a fat and makes it less brittle.

6) Volume contraction

When the bases are cooled in the mould volume of some bases may contract.

Volume contraction produces

(a) Good mold release facilitating the ejecting from mold.

(b) Contraction hole formation at the top: This imperfection can be solved by adding

slight excess base over the suppositories and after cooled the excess is scrapped off.

7) Lubricants

Cocoa butter adheres to suppository molds because of very low volume of

contraction. Aqueous lubricant may be used to remove the suppositories easily from

the molds. They are applied by wiping, brushing or spraying. The mold surfaces may

be coated with teflon to reduce the adhesion of base to mold wall.

8) Rancidity & oxidation

Suppositories

160

Due to auto oxidation of unsaturated fatty acids present in the base, saturated and

unsaturated aldehydes, ketones and acids may formed, which have very strong

unpleasant odor – this phenomenon is called rancidification. To prevent this suitable

antioxidants like hydroquinione, naphthoquinone, and tocopherols,gossypol (present

in cotton seed oil), sesamol (present in sesame oil) propyl gallate, gallic acid, tannins

and tannic acids, ascorbic acid (Vit C.), butylated hydroxyanisole (BHA) and

butylated hydroxyanisole (BHA).

Quality control of suppositories

Physical analysis

Visual examination

Color and the surface characteristics of the suppository are relatively easy to assess.

It is important to check for the absence of fissuring, pitting, mottling, cracks, air

bubbles, holes, fat blooming, exudation, sedimentation, homogeneity of the color,

and the migration of the active ingredients. A change in the odor may also be

indicative of a degradation process. Suppositories can be observed as an intact unit

and also by splitting them longitudinally.

Weight

Suppositories can be weighed on an automatic balance, obtaining the weight of 10

suppositories.

Suppositories

161

If the weight is found to be too small: it is advisable to check whether the mold is

being well filled and whether there are axial cavities or air bubbles caused by badly

adjusted mechanical stirring or the presence of an undesirable surfactant. It is also

important to check that the batch of suppositories is homogeneous.

If the weight is found to be too high: check that scraping has been carried out

correctly and also that the mixture is homogeneous.

Lastly, the weight may decrease during aging when the suppositories contain volatile

substances, especially if the packaging is not airtight.

Melting range (melting point, melting zone)

Melting range or melting zone is the term often preferred by some rather than

melting point. Many suppository bases and medicated suppositories are mixtures,

and so do not have a precise melting point.

In general, the melting point should be equal to or less than 37◦C. A non-destructive

method must be used because if the suppository is melted before a measurement is

made, the suppository constituents may be transformed into a metastable state.

The melting test consists of placing a suppository on the surface of water

thermostatically controlled at 37◦C and verifying the complete melting of the

suppository in a few minutes.

Chemical testing

Suppositories

162

Dissolution testing

One of the most important quality control tools available for in vitro assessment is

dissolution testing. Dissolution testing is often required for suppositories to test for

hardening and polymorphic transitions of active ingredients and suppository bases.

However, unlike for tablets and capsule dosage forms, there are not enough

dissolution testing methods or validations for suppositories. This can be partly due to

the immiscibility of some of the suppository vehicles in water. Dissolution test of

suppository can be done using the paddle, basket, and flow-through dissolution

methods.

Problems encountered with suppository dissolution test:

1) If the drug is immiscible in an aqueous dissolution fluid then it may require a

partitioning step; unfortunately this involves extra time, which alters the

dissolution rate calculation.

2) If a filtration step is involved in dissolution testing, the filtration membrane

may introduce an erroneous result between actual and obtained results as it

may clog.

3) Variations in density between the suppository and the receiving fluid must

also be considered.

Suppositories

163

Content uniformity testing

In order to ensure content uniformity, individual suppositories must be analyzed to

provide information on dose-to-dose uniformity. Testing is based on the assay of the

individual content of drug substance(s) in a number of individual dosage units to

determine whether the individual content is within the limits set.

References

Lachman/Lieberman’s The Theory and Practice of Industrial Pharmacy, Editors: Roop Khar,

SP Vyas, Farhan Ahmad, Gaurav Jain, Chapter 28 Kinetic Principles and Stability Testing,

Pg. No. 1036-1072, 2014.

Steven W. Baertschi and Patrick J. Jansen, Chapter 2 Stress Testing: A Predictive Tool,

Pharmaceutical Stress Testing (Predicting Drug Degradation), Taylor & Francis Group, LLC,

2005.

J.S Ptrick ; “Martin‟s Physical pharmacy and pharmaceutical sciences”;5th edition ;

published by Wolters Kluver Health(India)Pvt. Ltd. New Delhi. Page no – 428-432.

Steven W. Baertschi and Karen M. Alsante, Chapter 3 Stress Testing: The Chemistry of Drug

Degradation, Pharmaceutical Stress Testing (Predicting Drug Degradation), Taylor & Francis

Group, LLC, 2005.

ICH Q1B: Photostability Testing of New Drug Substances and Products.

ICH Q1C : Stability Testing of New Dosage Forms

Fathima N. et al., Drug-excipient interaction and its importance in dosage form development.

Journal of Applied Pharmaceutical Science 01 (06); 2011: 66-71.

Allen L. V and Ansel H. C. (2013). Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott Williams and Wilkins.

Taylor, K. M., and Aulton, M. E. (Eds.). (2017). Aulton's Pharmaceutics E-Book: The Design

and Manufacture of Medicines. Elsevier Health Sciences.

Porter, S. C. (2021). Coating of pharmaceutical dosage forms. In Remington The Science and

Practice of Pharmacy 23rd edition. (pp. 551-564). Academic Press. ISBN 978-0128200070.

Yihong Qiu, Yisheng Chen, Geoff G.Z. Zhang, Lirong Liu, William Porter, Developing

Solid Oral Dosage Forms: Pharmaceutical Theory & Practice, Pharmaceutical Theory and

Practice Series, Academic Press, 2009, ISBN 9780080932729

David B. Troy, Paul Beringer, Remington the science and practice of pharmacy, Lippincott

Williams & Wilkins, 2006, ISBN 9780781746731

Fridrun Podczeck, Brian E. Jones, Pharmaceutical Capsules Pharmaceutical Press, 2004,

ISBN 9780853695684.

Loyd Allen, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, Lippincott

Williams & Wilkins, 2014, ISBN 9781469871943David B. Troy, Paul Beringer,

Remington: The Science and Practice of Pharmacy, REMINGTON THE SCIENCE AND

PRACTICE OF PHARMACY, Lippincott Williams & Wilkins, 2006, ISBN 9780781746731

Gilbert S. Banker, Juergen Siepmann, Christopher Rhodes, Modern Pharmaceutics, Fourth

Edition, in Drugs and the Pharmaceutical Sciences, CRC Press, 2002, ISBN 9780824744694

Mansoor A. Kahn, Indra K. Reddy, Pharmaceutical and Clinical Calculations, 2nd Edition

Pharmacy Education Series, CRC Press, 2000, 9781420014792

http://www.google.com.eg/search?hl=ar&tbo=p&tbm=bks&q=inauthor:%22Yihong+Qiu%22&source=gbs_metadata_r&cad=5

http://www.google.com.eg/search?hl=ar&tbo=p&tbm=bks&q=inauthor:%22Yisheng+Chen%22&source=gbs_metadata_r&cad=5

http://www.google.com.eg/search?hl=ar&tbo=p&tbm=bks&q=inauthor:%22Geoff+G.Z.+Zhang%22&source=gbs_metadata_r&cad=5

http://www.google.com.eg/search?hl=ar&tbo=p&tbm=bks&q=inauthor:%22Lirong+Liu%22&source=gbs_metadata_r&cad=5

http://www.google.com.eg/search?hl=ar&tbo=p&tbm=bks&q=inauthor:%22William+Porter%22&source=gbs_metadata_r&cad=5

http://www.google.com.eg/search?hl=ar&tbo=p&tbm=bks&q=bibliogroup:%22Pharmaceutical+Theory+and+Practice+Series%22&source=gbs_metadata_r&cad=5

http://www.google.com.eg/search?hl=ar&tbo=p&tbm=bks&q=bibliogroup:%22Pharmaceutical+Theory+and+Practice+Series%22&source=gbs_metadata_r&cad=5

http://www.google.com.eg/search?hl=ar&tbo=p&tbm=bks&q=inauthor:%22David+B.+Troy%22&source=gbs_metadata_r&cad=6

http://www.google.com.eg/search?hl=ar&tbo=p&tbm=bks&q=inauthor:%22Paul+Beringer%22&source=gbs_metadata_r&cad=6

http://www.google.com.eg/search?hl=ar&tbo=p&tbm=bks&q=bibliogroup:%22REMINGTON+THE+SCIENCE+AND+PRACTICE+OF+PHARMACY%22&source=gbs_metadata_r&cad=6

http://www.google.com.eg/search?hl=ar&tbo=p&tbm=bks&q=inauthor:%22Fridrun+Podczeck%22&source=gbs_metadata_r&cad=7

http://www.google.com.eg/search?hl=ar&tbo=p&tbm=bks&q=inauthor:%22Brian+E.+Jones%22&source=gbs_metadata_r&cad=7

http://www.google.com.eg/search?hl=ar&tbo=p&tbm=bks&q=inauthor:%22Loyd+Allen%22&source=gbs_metadata_r&cad=5



http://www.google.com.eg/search?hl=ar&tbo=p&tbm=bks&q=inauthor:%22Gilbert+S.+Banker%22&source=gbs_metadata_r&cad=4

http://www.google.com.eg/search?hl=ar&tbo=p&tbm=bks&q=inauthor:%22Juergen+Siepmann%22&source=gbs_metadata_r&cad=4

http://www.google.com.eg/search?hl=ar&tbo=p&tbm=bks&q=inauthor:%22Christopher+Rhodes%22&source=gbs_metadata_r&cad=4

http://www.google.com.eg/search?hl=ar&tbo=p&tbm=bks&q=inauthor:%22Christopher+Rhodes%22&source=gbs_metadata_r&cad=4

http://www.google.com.eg/search?hl=ar&tbo=p&tbm=bks&q=bibliogroup:%22Drugs+and+the+Pharmaceutical+Sciences%22&source=gbs_metadata_r&cad=4

http://www.google.com.eg/search?hl=ar&tbo=p&tbm=bks&q=inauthor:%22Mansoor+A.+Kahn%22&source=gbs_metadata_r&cad=6

http://www.google.com.eg/search?hl=ar&tbo=p&tbm=bks&q=inauthor:%22Indra+K.+Reddy%22&source=gbs_metadata_r&cad=6

http://www.google.com.eg/search?hl=ar&tbo=p&tbm=bks&q=bibliogroup:%22Pharmacy+Education+Series%22&source=gbs_metadata_r&cad=6

1

Contents

Lab 1 Problems on Reaction kinetics and stability

Lab 2: Problems on Reaction kinetics and stability

Lab 3: Measurement of powder flowability (Angle of repose- Bulk density)

Lab 4: Preparation of dusting powder

Lab 5: Effervescent granules

Lab 6: Medicated Effervescent granules

Lab 7: Molded tablets

Lab 8: Cacao butter suppository and calculation of displacement value

Lab 9: Glycero-gelatin (water soluble-base )suppository

Lab 10: Zinc oxide pessaries

2

Lab1: Problems on Reaction kinetics and stability

Zero-order reaction

It is also called as constant rate process.

The reaction is said to be zero-order reaction, if the rate of reaction is independent

of the concentration i.e. the rate of reaction cannot be increased further by

increasing the concentration of reactants.

In this type of reaction, the limiting factor is something other than concentration.

dc/ dt= -Ko C = -Ko

Where

Ko = zero-order rate constant (in mg/mL.min)

Rearrangement of the above equation yields:

dc= -Ko dt

Integration of this equation gives:

C - Co = - k0 t

or

C = Co - k0 t

Where Co = concentration of drug at t = 0 (initial concentration).

C = concentration of drug yet to undergo reaction at time t (remaining

concentration at time t).

3

K0 units: mg ml-1

year−1

A plot of C Vs time results in straight line with slope equal to K.

The value of K indicates the amount of drug that is degraded per unit time, and

intercept of line at time zero is equal to constant


Let C = Co /2 and t½ = t

Substitute in equation; C = Co – k t

C = C0 at (t = t1/2)

C0 = C0 – kt1/2

kt1/2 = C0 - C0 = C0

4

t1/2 =

Note: Rate constant (k) and t½ depend on Co


Let C = 0.9 Co and t= t0.9

substitute in equation; C = Co –k t

C = 90% C0 = 0.9 C0

0.9 C0 = C0 - K t90%

K t90% = C0 – 0.9 C0 = 0.1 C0

t90% =

First order reaction

Whose rate is directly proportional to the concentration of the drugs undergoing

reaction i.e. greater the concentration, faster the reaction.

The most common pharmaceutical reactions e.g; drug absorption & drug

degradation

First-order process is said to follow linear kinetics

dC/dt= - KC

Where K = first-order rate constant (time -1

)

Integrating above rate equation between initial concentration Co at t = 0 & C,

concentration after t=t, we obtain:

5

ln C- ln Co= -Kt

Log C= Log C0 - k t/2.303

When this linear equation is plotted with „log C‟ on vertical axis against „t‟ on

horizontal axis, the slope of the line is equal to= -kt/2.303

K Units: year -1


Let t = t½ and C = C0 /2

substitute in Log C= Log C0 - k t/2.303

Log C = log C0 -

C = C0 at (t = t1/2)

log ½ C0 = log C0 -

= log C0 – log ½ C0

= log = log 2

6

t1/2 =

t1/2 =

K = 0.693 / t½


Let t = t0.9 C = 0.9 Co

substitute in: Log C= Log C0 - k t/2.303

t0.9= 0.105 / K

K = 0.105/ t0.9

Give answer for the following problems:

1. Using the integrated form of the rate law, determine the rate constant k of a

zero-order reaction if the initial concentration of substance A is 1.5 M and after 120

seconds the concentration of substance A is 0.75 M.

7

2. Using the substance from the previous problem, what is the half-life of

substance A if its original concentration is 1.2 M?

3. Given are the rate constants k of three different reactions:

Reaction A: k = 2.3 M-1

s-1

Reaction B: k = 1.8 Ms-1

Reaction C: k = 0.75 s-1

Which reaction represents a zero-order reaction?

8

4. The half-life of a first-order reaction was found to be 10 min at a certain

temperature. What is its rate constant?

9

Lab2: Problems on Reaction kinetics and stability

Answer the following problems

5. If 3.0 g of substance A decomposes for 36 minutes the mass of unreacted A

remaining is found to be 0.375 g. What is the half life of this reaction if it

follows first-order kinetics?

6. Calculate the half-life of the reactions below:

a- If 4.00 g A are allowed to decompose for 40 min, the mass of A remaining

undecomposed is found to be 0.80 g.

b- If 8.00 g A are allowed to decompose for 34 min, the mass of A remaining

undecomposed is found to be 0.70 g.

10

7. A Pharmaceutical company has just produced a new vitamin tablet containing

5mg riboflavin and 500mg vitamin C. They have been having problems with the

stability of this product. After 4 days in a bottle (at 25°C), the tablet turns brown and

the amount of riboflavin declines to 4mg.

1. Analytical chemists have determined that the riboflavin in the tablet is

photolyzed by a first-order process. Based only on the riboflavin in the current

formulation, what is the shelf-life if 10% degradation is acceptable?

2. How long would it take for the amount of riboflavin to decrease by

99%?

8. A certain reaction is first order, and 540. seconds after initiation of the reaction,

32.5% of the reactant remains. What is the rate constant for this reaction? At what

time after initiation of the reaction of the reaction will 10.0% of the reactant remain?

11

Lab 3:Measuring powder flow properties

On small scale, evaluation of powder flow can be done by the measurement of:

1- Bulk density

2- Angle of repose.

1- Bulk density

We evaluate the flowability of the powder by comparing the poured (fluff) density

(ρ poured) and tapped density.

Calculate carrˊs index % and Huasner ratio whose values indicate powder flow as

shown in the table (A):

Carrˊs index (%) = { ρ tapped- p poured/ ρ tapped} x 100

Huasner ratio = ρ tapped / ρ poured

Table (A): Carrˊs index as an indication of powder flow properties

N.B. flow of powder may be improved by adding glidiant, ex: 0.2% Aerosil.

carrˊs index (%) Type of powder flow

5-12 Excellent

13-16 Good

17-21 Fair to passable

22-35 Poor

36-38 Very poor

>40 Extremely poor

12

For Huasner ratio, values less than 1.25 indicate good flow, while values greater

than 1.25 indicate poor flow.

Values between 1.25 and 1.5, adding glidant normally improve the flow.

Procedure:

1- Weigh 10 g of the powder

2- Pour gently in 50 ml measuring cylinder

3- Get volume poured V, and then calculate poured density.

ρ poured = mass/ V poured

4- Tap till constant volume

5- Get volume tapped and calculate density

ρ tapped = mass / V tapped

6- Calculate the carrˊs index and Huasner ratio

7- Repeat for different powders

8- Comment on their values

Powder

no.

V

poured

V

tapped

ρ

poured

Ρ

tapped

carrˊs

index

Hausner

ratio comment

1

2

3

4

5

13

Angle of repose:

When certain weight of powder is left to flow vertically, with only gravity acting

upon it, it will tend to form a conical mound. On condition that the angle to

horizontal cannot exceed certain value characteristic for each powder, and it is

known as angle of repose (θ).

Any particle lies outside this limiting angle will slide down the adjacent surface

under the influence of gravity until the gravitational pull is balanced by the inter-

particulate friction forces. Accordingly there is a relationship between θ and the

ability of the powder to flow as shown in table (B).

Table (B): Angle of repose as an indication of powder flow properties

Angle of repose Type of flow

<20 Excellent

20-30 Good

30.34 Passable

>40 Very poor

N.B. May be improved by adding glidant, ex: 0.2% Aerosil

Determination of the angle of repose

The angle of repose can be determined by different methods, the most important is

the fixed funnel method:

Procedure:

a- Fix a funnel on a stand at height (h) 2 cm from the base.

14

b- Pour the powder slowly at constant rate on walls of the funnel.

c- Measure the diameter ( d) of the circular base formed by the cone of the

powder

d- Repeat measuring 3 or 4 times, then calculate the average

e- Calculate tan θ= h//r where (r) is radius of the cone base

f- Repeat for different powders

g- comment on their values

Powder

no.

Average

diameter

(d)

R = d/2 Tan θ Θ comment

1

2

3

4

15

Lab 4:Preparation of medicated dusting powder

What Is Medicated Dusting Powder?

Body dusting powders have a wide appeal because of smooth feeling and cooling

effect, which they impart while they temporarily adsorb moisture. The cooling effect

is due to extra heat loss due to large surface area of talc particles.

Talc is a major ingredient in medicated dusting powder formulation, which should

have good slip characteristics, covering power and body adhesion. The slip and

adhesion properties of medicated dusting powder essentially depend on talc.

It is essential then to use grid free, alkali free high quality cosmetics talc in

preparation of medicated dusting powder. Talc should be free from bacteria and

therefore sterilized grades should only be used.

In order to improve adhesion properties, metallic stearates such as Zinc stearate or

Magnesium stearate and kaolin are incorporated. To improve adsorbency,

Magnesium carbonate [Mg (Co)3], starch, kaolin and precipitated chalk are used in

combination. Zn oxide and Titanium dioxide (TiO2) at low levels along with earth

colors can be incorporated and should be sufficiently powerful to cover the base

odour. Other ingredients sometimes included are boric acid to act as skin buffering

agent and fused silica to give powder a lower density; salicylic acid is added as

antibacterial agent. Aluminum chloride (AlCl3) is used as an antiperspirant.

The label for dusting powder should display the following information

1. Name of the product :- Medicated Dusting Powder

2. Contents: Name and percentage of any active ingredient if added to

preparation. In this case.

16

3. Net Weight: As present in the final container.

4. Manufacturing Batch Number: As applicable

5. Manufacturing Date – Month and year of manufacturing.

6. Expiry Date – Month and year of expected expiry.

General method for preparing dusting powders

The method for mixing powders in the formulation of a dusting powder is the

standard „doubling-up‟ or „geometric dilution‟ technique.

„Doubling-up‟ technique:

1. Weigh the powder present in the smallest volume (powder A) and place in the

mortar.

2. Weigh the powder present in the next largest volume (powder B) and place on

labeled weighing paper.

3. Add approximately the same amount of powder B as powder A in the mortar. Mix

well with pestle.

5. Continue adding an amount of powder B that is approximately the same as that in

the mortar and mix with the pestle, i.e. doubling the amount of powder in the mortar

at each addition.

6. If further powders are to be added, add these in increasing order of volume as in

parts 3, 4 and 5 above.

Medicated dusting powder Formulae:

Formula 1

Preparation of Zinc, Starch and Talc Dusting Powder (B.P):

R/

Zinc Oxide BP 25 g

17

Starch BP 25 g

Purified Talc BP 50 g

Send 20 gm

Calculations:

Procedure

Use of prescription:

Label

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Formula 2

Preparation of Salicylic acid Dusting Powder (B.P):

R/

Salicylic acid 10 g

18

Kaolin 15

Starch BP 25 g

Purified Talc BP 50 g

Send 20 gm

Calculations:

Method

Use of prescription:

Label

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-----------------------------------------------------------------------------------------

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19

Lab 5: Effervescent granules

The effervescent granules are popular in use due to its taste and carminative effect.

It is a mixture of citric and tartaric acids with` bicarbonate of soda and usually some

medicaments and occasionally sugar.

It is decided that citric acid and tartaric acid are to be used in ratio of 1:2

respectively. The amount of sodium bicarbonate to be used may be calculated from

the equation of the reaction:

3 NaHC03 + C6H807.H20 → C6H5Na307 + 3 C02 + 3 H20

(Sodium bicarbonate) (Citric acid) → tri-sodium citrate+ carbon dioxide+ water

(3 x 84) (210)

Setting up a proportion to determine the amount of sodium bicarbonate that will

react with 1 g of citric acid, one has:

210/ 1 = 3 x 84/ amount of sodium bicarbonate

Amount of sodium bicarbonate = 1.2g

Similar calculations show that 2.24 g of sodium bicarbonate react with 2 g of tartaric

acid. Thus, with the acids in ratio of 1:2 it has been calculated that 3.44 g of sodium

bicarbonate is necessary to react with the 3 g of combined acids. To enhance the

flavor, the amount of sodium bicarbonate may be reduced to 3.4 g to allow a tartaric

acid taste.

20

For preparation of effervescent granules, citric acid should be powdered just prior to

use. Sodium bicarbonate and other ingredients should be powdered and dried at 100

⁰C until they cease to lose weight

The methods used for preparation of effervescent granules are fusion method or wet

method.

Preparation of effervescent granules

Fusion method

1) Mix the four powders homogenously in a porcelain dish and transfer to

boiling water-bath.

2) The mixture of the powders is continuously triturated while on the water bath.

When the mass adjacent to heat seems doughy, turn over so as to allow the

release of all water of crystallization of citric acid

3) The point, at which the mass seems dough, is considered critical. At such

time, the dish is removed from heat and the dough is quickly forced through

sieve No. 10. The collected granules are dried

4) The dried granules are shaken gently over sieve No. 20 and the non-passed

granules are collected for further investigation.

Wet method

1) Grid each powder first separately

2) Wight each one and put the amounts needed in the porcelain dish

3) Mix all of them by hand not pestle.

4) Add drops of ethanol 95% until the mass coheres as small granules lump

5) Press with your hands in sieve No. 10 to make rod shape.

6) Shake the granules over sieve No. 20 to discard the small fine particles.

7) Leave granules to dry.

Evaluation of the granules

21

1- Transfer accurately weighed 0.25 g of granules into a clean dry 100 ml

measuring cylinder.

2- Add 5 ml of distilled water to the granules and record the following

parameters

Time required starting the effervescence.

The volume of the liberated CO2

Time required until effervescence stopped

The clarity of the solution after complete effervescence

3- Repeat the test for other granules prepared by wet granulation and tabulate

your results.

Preparation of effervescent granules by fusion and wet method

Send 20 g of effervescent sodium citro-tartarate granules using once wet granulation

technique and another using fusion method.

Compare between the two forms of granules for effervescence powder, and

effervescence time.

R/

Sodium bicarbonate------------------- 510 g

Citric acid------------------------------- 180 g

Tartric acid ------------------------------270 g

Sucrose-----------------------------------150 g

Send 20 g

Calculations

22

The total weight of the above formula is 1110 g. This will be reduced to about 1000

g due to interaction and subsequent loss in weight.

The quantity required is 20g, an excess of 25% is prepared to counteract loss during

preparation, and therefore 25g are prepared. So, multiply each of the above

ingredients by 25/1000.

Formula ingredients:

Use of the prescription:

Granules evaluation:

Tabulate your results using the following table:

Method of

preparation

Time required

starting the

effervescence

Effervescence

time

Volume of

effervescence

Clarity of the

solution

Fusion

Wet

23

Label:

---------------------------------------------

24

Lab 6: Medicated Effervescent granules

Prescription 2- Hematopoietic effervescent granules:

Rx/ prepare 20 g of effervescent sodium citro-tartarate containing 5%, 10% of iron

ammonium citrate.

Calculation:





25

Method of

preparation

Time required

starting the

effervescence

Effervescence

time

Volume of

effervescence

Clarity of the

solution

Fusion

Wet

Label:

---------------------------------------------

Prescription 3- Magnesium-sulphate effervescent granules:

Rx/ prepare 20 g of effervescent sodium citro-tartarate containing 20% of

magnesium sulphate.

Calculation:

26





Method of

preparation

Time required

starting the

effervescence

Effervescence

time

Volume of

effervescence

Clarity of the

solution

Fusion

Wet

Label:

---------------------------------------------

27

Prescription 4- Acetylsalicylic acid (aspirin) effervescent granules:

Rx/ prepare 20 g of effervescent sodium citro-tartarate containing 1% of

Acetylsalicylic acid

Calculation:





Method of

preparation

Time required

starting the

effervescence

Effervescence

time

Volume of

effervescence

Clarity of the

solution

Fusion

Wet

28

Label:

---------------------------------------------

29

Lab 7: Molded tablets

It is sometimes called tablet triturate. They are usually prepared of some

medicaments, diluted with lactose.

Apparatus:

An upper plate with perforations, corresponding in size, position and number with a

range of pages fixed in a lower plate. Two large pages ensure correct fitting of the

plates. Plates are deigned to prepare 50-250 tablet in one time.

Procedure:

1) The medicated lactose is made into dough mass with 70% alcohol.

2) Force the dough mass into the perforation, a spatula is used to ensure that

each cavity is filled and smooth of excess.

3) The filled plate is then superposed and passed down, thus leaving the paste in

the form of tablets, resting on the pages.

4) The tablets are left there to dry for one hour and then packed into pill-boxes.

Calibration of the mold

This is determined using lactose and 70% alcohol. (Leave tablets to dry for one

hour, to ensure complete volatilization of the alcohol).

Displacement value of the medication

The displacement value is the proportion of the medication, which displaces one

part of lactose. Its calculation is important when the proportion of medication is

high and its density differs considerably from that of lactose. It is ignored when

proportion of medication is small. It is determined as follow:

1- Prepare an admixture of 10 or 20% of medication with lactose.

2- Make into tablets, dry and weigh.

3- Make an equal number of tablets with lactose and weigh

4- Calculate the displacement value as stated in the following example:

30

a- Ten tablets, containing 20% of calomel and 80% lactose weighed 1.215 g.

the composition of 10 tablets is therefore 0.243 g calomel and 0.972 g

lactose.

b- New 10 tablets containing lactose only = 1.037 g.

The calomel has therefore displaced 1.037-0.972 = 0.065 g of lactose.

c- The displacement value of calomel is 0.243/0.065= 3.74.

Prescription 1:

Prepare 15 plain and 15 medicated molded tablets containing 5% ferric ammonium

citrate, then calculate the displacement value of this medication with respect to

lactose.

Calculations:

Assume each tablet weight is 100 mg.

Procedure:

Follow the general procedure for preparation.


Label:

31

---------------------------------------------

Prescription 2:

Prepare 20 tablets, each containing 20 mg of calomel (D.V. 3.8)

Calculations:


Procedure:



32

Label:

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Prescription 3:

Prepare 20 tablets, each containing 5%, 7%, 10% of iron ammonium phosphate

Calculations:


Procedure:


33


Label:

---------------------------------------------

34

Lab 8: Cacao butter Suppositories and Calculation of displacement value

Suppositories are molded solid medicated preparations designed for insertion in

rectum where they melt, dissolve or disperse and exert local or systemic effect.

Pessaries are similar solid medicated preparation designed for insertion into the

vagina usually exert local effect also can be used for systemic delivery of drugs,

they are prepared in the same way as suppositories but they are larger in size with

cone shaped and rounded tip.

Compounding of suppositories and pessaries

Preparation of suppositories and pessaries in small scale are done in molds which

are made of metal and usually have six (occasionally twelve) cavities.

The nominal capacities of the commonly used mold are 1 gram (infants), 2 gram

(adults), and 4 gram (for vaginal pessaries).

Calibration of the mold

Calibration with cacao butter is necessary for all molds; this calibration depends on

the calculation of the displacement value of all ingredients incorporated with the

base of the suppository, thus ensuring the admixing of exact dose of each ingredient.

Procedure:

1- Make sure that the two halves of the suppository molds are exactly coinciding

so that no openings are detected when tightly closed mold is examined against

light.

2- Lubricate the mould with the soap solution by piece of muslin.

3- Invert the mould on a porcelain slab to allow any excess of the lubricating

solution to drain.

35

4- Weigh an amount of cacao butter slightly more than calculated amount of a

certain number of suppositories according to tile figure engraved on the

mould.

5- Shred this amount of cacao butter and melt 2/3 of the amount, in a porcelain

crucible by exposing the crucible for few seconds to steam of boiling water

bath, then remove crucible from the steam and triturate with glass rod.

6- Pour gradually in a continuous stream the melted base into the well lubricated

mould; let the melted mass overflow to avoid formation of holes after

cooling.

7- Cool the filled mould in a refrigerator for 15 minutes by the heated end of the

spatula remove the excess of cacao butter.

8- Open the mould and allow the prepared suppositories to slide from the mould

by slight pressing on the tip of the suppository.

9- Weigh accurately a certain number of suppositories and then calculate the

average weight in order to obtain the correction factor, divide the mean

average weight by nominal capacity of the mould. It must be equal 1.

Lubrication of mold:

Lubricating the cavities of the mould is helpful in producing elegant

cacao butter suppositories free from surface depression.

The lubricant must be different in nature than suppository mass or it

will become absorbed and will fail to provide a buffer film between

mass and metal consequently.

An oily lubricant is useless for cacao butter suppositories

The following has been found satisfactory:

Soft soap:

Glycerin-------------------------- 1 part

36

Alcohol (90%)------------------5 part

This lubricant is quite unsuitable for use with gelato-gelatin mass as

mentioned above, and for this it is necessary to use oil as liquid

paraffin, olive, or almond oil.

The lubricant should be applied on pledged of gauze or with fairly stiff

brush.

N.B.

Soft soap liniment should never be used for suppository containing

metallic salts, because a reaction occurs between the soap and salt. An

alcoholic solution of castor oil is a good substitution in this case.

Carbowaxes and tweens shrink slightly on cooling and draw away from

the mould, so lubricant is not necessary

When a dusting powder is used as lubricant, starch is the one of choice.

It should be sprinkled lightly, avoiding excess. Talc or lycopodium

shouldn‟t be used because they tend to produce non healing

granulomatous lesions when used in rectal or vaginal suppositories.

Calculation of displacement value of solid medicaments in suppositories:

The volume of suppositories from a particular mold is obviously

uniform, but its weight would vary according to the density of

medicaments, so compared with the base with which the mold is

lubricated.

The products made from molds cannot be prepared accurately unless

allowance is made for the alteration in density of the mass due to added

medicaments.

37

The quantity of medicaments which displace one part of the base is

called the displacement value.

The displacement value is determined as follow:

1- Prepare and weigh 3 suppositories of cacao butter or other base= (a) gram

2- Prepare and weigh 3 suppositories containing 10% of medicament = (b)

gram

3- Calculate the amount of cacao butter (c) gram

4- Calculate the medicament amount(d) gram

5- Now a-c= the weight of cacao butter base displaced by (d) gram

6- Displacement value of medicament = d/a-c

Example

1- Weight of 3 suppositories = 3 g

2- Weight of 3 suppositories containing 10% medicament = 3.2 g

3- Weight of cacao butter in medicated suppositories = 3.2X90/100=2.88 g

4- Weight of medicament in medicated suppositories= 3.2-2.88= 0.12 g

5- 0.12 g of cacao butter displaced by 0.32 g medicament

1 cacao butter is displaced by X medicament

X= 1x 0.32/0.12 = 2.66

Compounding problems with cacao butter suppositories:

1) Lowering melting point

2) Raising melting point

3) Use of solvents

Lowering melting point

38

The melting point of theobroma oil is lowered by the addition of volatile oil

and certain soluble substances such as camphor, chloral hydrate and phenol

The extent of the effect of these substances on melting point depends upon

the amount added, this is difficult to correct and in such cases it is better to

make the suppositories by hot process and to allow the poured suppositories

to congeal under refrigeration, however the spermaceti or wax raises the

melting point so that the suppository may be made by usual methods.

Less than 18% spermaceti lowers melting point of theobroma oil, when 26%

is added, the resulting melting point of the mixture is identical with that of the

pure theobroma oil, over 28% of spermaceti raises the melting point above

body temperature.

Wax raises the melting point of suppository but since it gradually hardens on

standing it is less desirable than spermaceti.

Less than 3% wax lowers the melting point of theobroma oil, while more than

5% raise it

Above 37 C, therefore about 4%should be used.

In order to be certain that the mixture doesn‟t have too high melting point, it

may be tested by placing some of the mass in water at 37 c, if it doesn‟t melt,

less spermaceti or wax should be used.

Raising of melting point

Silver nitrate and lead acetate are among chemicals that raise the melting

point of theobroma oil above body temperature

The addition of small amounts of peanut oil or some similar bland oil will

lower the melting point below body temperature.

Prescription 1: zinc oxide suppository

Rx.

39

Calculate the displacement value of 3 suppositories containing 10% zinc oxide using

cacao butter as a base.

Fait. Suppository

Sig. one suppository p.r.n.

Calculations:

Procedure


Label:

40

---------------------------------------------

Prescription 2: tannic acid suppository

Rx

Tannic acid----------------------------0.1 g

Cacao butter ---------------------------Q.S

Fait. Suppository

Mitte III

Sig. one suppository p.r.n.

N.B. DV of tannic acid = 1.6

Calculations:

Procedure

41


Label:

-----------------------------------------------------------------------------------------------------

-----------------------------------------------------------------------------------------------------

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42

Lab 9: Water soluble bases suppositories

1- Glycerol-gelatin base:

It is a mixture of glycerin and water gelled with gelatin. This base doesn‟t melt in

the body but dissolves in the aqueous solution and provide continuous release of

the drug.

Disadvantages:

1- Unpredictable dissolution time which varies with the batch of gelatin and age

of base.

2- Hygroscopic and so produce some irritation due to dehydration effect of the

mucosa and ir must be protected from moisture.

3- Favored mold and bacterial growth

4- Has laxative effect

5- Long preparation time

6- No significant concentration on cooling and hence it needs a good ion of the

lubrication of the mould.

N.B.

A gelatin base is incompatible with many substances prescribed in

suppositories as tannic acid, ferric chloride and gallic acid so it is less

frequently used than cacao butter.

Glycerin suppository could be used in its plain form as laxative for children.

Correction for capacity of mould with gelatin base:

a) Weigh the required amount of gelatin and soak it in enough water

until softened.

b) Put soaked gelatin on the calculated amount of glycerin previously

weighed in crucible, on water bath until gelatin dissolves and

constant weight is obtained. During evaporation, the liquid mass

43

should be only gently stirred, rapid stirring produce air bubbles

which may appear in the finished suppository.

c) Remove any skin formed on the surface before pouring.

d) Pour the mass while still hot into the holes lubricated with liquid

paraffin, let the melted mass to over flow.

1- Fill the other 3 holes lubricated with soap solution with cacao butter, cool

both kinds of suppositories and remove over flow.

2- Open the mould and weigh separately the individual suppositories then

calculate the average weight of each kind.

3- Clean the mould and lubricate now with liquid paraffin only and prepare 5

grams of the B.P.C. and U.S.P. formula and calculate the average weight

of 3 suppositories of each kind.

4- Calculate the factor of correction for capacity of mould with each of the

three gelatin bases as follow:

Factor of correction= Average weight of any gelatin suppository/ average

weight of cacao butter

I- Glycerin suppository B.P.

Gelatin-------------------- 14 g

Glycerin------------------- 70 g

Water Q.S. to---------------- 100ge

This is suitable bas for medicated suppositories containing solid medicament or not

more than about 20% of semisolid or liquid medicament with more than this mass

becomes too soft.

44

II- Gelato-glycerin B.P.C.

Gelatin----------------------25 g

Glycerin----------------- 40 g

Water Q.S. to------------ 100g

This is a stiffer mass and is, therefore, used for suppositories and pessaries

containing 20% or more of a semisolid or liquid medicament.

III- Glycerinated gelatin U.S.P.

Gelatin-------------------- 20 g

Glycerin-------------------- 70 g

Water Q.S. to------------ 100 g

Calculations:

Label:

---------------------------------------------

45

N.B.

Glycerogelatin base is hygroscopic so an auxiliary label “store in cool and dry place

in a tightly closed container” is necessary for all supp. Made of this base.)

Boroglycerin suppository:

R/

Boric acid 7.5 g

Gelatin 15 g

Glycerin 62.5 g

Water 15 g

Fiat: suppository mitte III

Sig: unum omni nocte adhibendus

Boric acid reacts with glycerin on heating giving glyceryl borate.

Calculations:

The formula gives 100 g of suppository mass to prepare 3 suppositories.

Calculate for 5

Amount of boric acid = (7.5 x 5)/100=

Amount of gelatin= (15x5)/100=

Amount of glycerin= (62.5 x 5)/100=

Method of preparation:

Soak the gelatin in water until thoroughly softened and transfer over a water bath,

dissolve boric acid in glycerin by the aid of gentle heat and add the gelatin solution.

Heat until a clear solution is produced and constant weight is attained. Then pour

into lubricated moulds avoiding overfilling.

46

Lab 10: Zinc oxide pessaries

Zinc oxide pessaries:

R/

Zinc oxide 0.5 g

Glycerogelatin base Q.S

Fiat pessaries mitte III

Sig. O.N.

Calculation

Made for 5 pessaries

D.V. of ZnO=5

Amount of drug= 0.5x 5= 2.5gm

Amount of base = [(5x4)- 2.5/5) x 1.2= 23.4 g

Wt of gelatin = 23.4 x 14/100 = 3.3g

Wt of glycerin= 3.7 ml

Procedure:

1- Lubricate the mould with liquid paraffin and invert it.

2- Soak the gelatin in water for 15 minutes.

3- Levigate ZnO with little amount of the glycerol on a tile using flexible

spatula.

4- Heat the remainder of glycerol to 100 C.

5- Add the heated glycerol to the soaked gelatin, put on a eater bath, stir

gently until the gelatin dissolves and a constant weight is obtained

(evaporation of excess water).

6- Add the drug levigate and mix.

7- Pour into the mould, no overflow.

8- Cool and remove from the mould.

pharmaceutics iii pt 506 - elearning.mti.edu.eg

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