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STAGES OF PHARMACEUTICAL MANUFACTURING

API

Excipients

PrimaryPackaging

SecondaryPackaging

API FinishedProduct

Starting Materials(Chemicals)

PHARMACEUTICAL MANUFACTURING OF NORMAL DOSAGE FORMS

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Dosage Forms

Tablets/Capsules

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Injectables

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Inhalants

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Transdermal products and implants

Skin

Drug

1. SOLID DOSAGE FORMS

Oral

Tablets

Lozenges

Chewable tablets

Effervescent tablets

Multi-layer tablets

Modified release

Capsules

Hard gelatin

Soft gelatin

Powders

Inhaled

Aerosol

Metered dose inhalers

Dry powder inhalers

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Drug substances are most frequently administered as solid dosage formulations,mainly by the oral route. Tablets and capsules are the most frequently used soliddosage forms, have been in existence since the nineteenth century, and are unitdosage forms, comprising a mixture of ingredients presented in a single rigid entity,usually containing an accurate dose of a drug. There are other types of solid dosageforms designed to fulfill specific delivery requirements, but they are generallyintended for oral administration and for systemic delivery. The major solid oral dosageform is the tablet, and these can range from relatively simple, single, immediate –release dosage forms to complex modified - release systems. Tablets offer advantagesfor both patients and manufacturers

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ADVANTAGES OF TABLETS AS A DOSAGE FORM

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Tablets are classified by their route of

administration or their function, form, or

manufacturing process. For example, some

tablets are designed to be placed in the oral

cavity and to dissolve there or to be chewed

before swallowing, andthere are many kinds of

formulation designed for sustained or

controlled release

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Dissolution of the drug must occur before or on reaching the absorption site before absorption canoccur, and generally water - soluble drugs do not exhibit formulation difficulties. For poorly water -soluble drugs, the absorption rate may be dictated by the dissolution rate, and, if dissolution isslow, bioavailability may be compromised. The solubility of a drug should, therefore, be consideredalong with its dose when designing formulations, and unsuitable biopharmaceutical properties isthe major reason for the failure of new drugs.

According to the Biopharmaceutics Classification System (BCS), drug substances are classified asfollows :

Class I: high permeability, high solubility

Class II: high permeability, low solubility

Class III: low permeability, high solubility

Class IV: low permeability, low solubility 8

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EXCIPIENTS IN SOLID DOSE FORMULATIONS

In addition to the active ingredients, solid oral dosage forms will also contain arange of substances called excipients. The role of excipients is essential in ensuringthat the manufacturing process is successful and that the quality of the resultantformulation can be guaranteed. The appropriate selection of excipients and theirrelative concentrations in the formulation is critical in development of a successfulproduct.

Although they are often categorized as inert, preformulation studies can determinethe influence of excipients on stability, bioavailability, and processability. Excipientsare categorized into groups according to their main function

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1.1. COATED TABLETS

Tablets are often coated to protect the drug from

the external environment, to mask

bitter tastes, add mechanical strength, or

to enhance ease of swallowing. A coating

can also be used for aesthetic or commercial

purposes, improving product appearance and

identity.

a) Sugar Coated Tabletsb) Film Coated Tabletsc) Compression Coating and Layered Tabletsd) Tablet Wrapping

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1.2. HARD AND SOFT GELATIN CAPSULES

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Capsules are solid oral dosage forms in which the drug is enclosed within ahard or soft shell. The shell is normally made from gelatin and results in asimple, easy - to swallow formulation with no requirement for a furthercoating step.

They can be either hard or soft depending on the nature of the capsule shell,with soft capsules possessing a flexible, plasticized gelatin film. Hard gelatincapsules are usually rigid two - piece capsules that are manufactured in oneprocedure and packed in another totally separate operation, whereas theformulation of soft gelatin capsules is more complex but all steps areintegrated.

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Liquid Excipients Compatible with Hard

Gelatin Capsules

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1.3. EFFERVESCENT

TABLETS

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Effervescence is the reaction in water of acids and bases to produce carbon dioxide,and effervescent tablets are dissolved or dispersed in water before administration.Advantages of effervescent formulations over conventional formulations are that thedrug is usually already in solution prior to ingestion and can therefore have a fasteronset of action. Although the solution may become diluted in the GI tract, anyprecipitation should be as fi ne particles that can be readily redissolved. Variability inabsorption can also be reduced. Formulations can be made more palatable and therecan be improved tolerance after ingestion. Thus, the types of drugs suited to thisformulation method are those that are difficult to digest or are irritant to mucosa.Analgesics such as paracetamol and aspirin and vitamins are common effervescentformulations. The inclusion of buffering agents can aid stability of pH sensitive drugs.There is also the opportunity to extend market share and to deliver large doses ofmedication.

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1.4. CHEWABLE TABLETS

Chewable tablets are designed to be mechanically

disintegrated in the mouth.Potential advantages of

chewable tablets are mainly concerning patient

convenienceand acceptance, although

enhanced bioavailability is also claimed.

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2. SEMI-SOLID DOSAGE FORMS

Ointments, creams, paste and gels aresemisolid dosage forms intended fortopical application. They may be applied tothe skin, placed on the surface of the eye,or used nasally, vaginally, or rectally. Mostof these preparations are used for theeffects of the therapeutic agents theycontain. The un-medicated ones are usedfor their physical effects as protectants orlubricants. Topical preparations are used forboth local and systemic effects.

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PHARMACEUTICAL OINTMENTS AND PASTES

Pharmaceutical ointments are semisolid systems that are applied externally,primarily to the skin and also to mucous membranes, e.g. The rectum, thevagina/vulva, the eye. Typically, medicated ointments are used for the treatment ofinfection, inflammation and pruritus. However, non-medicated ointments arecommonly used due to their emollient/lubricating properties. Pharmaceuticalpastes are generally composed of ointment bases that contain a high concentration(frequently 50% w/w) of dispersed drug. The viscosity of pharmaceutical pastes isgreater than that of pharmaceutical ointments.

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ADVANTAGES

1) Pharmaceutical ointments may be easily spread on skin, being retained at the siteof application as an occlusive layer, thereby preventing moisture loss from the skin.This is particularly useful whenever restoration of the physical characteristics ofthe skin is required (e.g. due to inflammation).

2) Pharmaceutical ointments are associated with lubricating properties, propertiesthat may be employed to reduce trauma of an affected site upon spreading.

3) In general, pharmaceutical ointments persist at the site of application, enablingthe duration of drug release to be greater than for many other topical dosageforms. The increased viscosity of pharmaceutical pastes ensures that a thick film ofthe dosage form is applied to the site of action, which shows excellent persistence.This property is particularly useful if protection of an inflamed site is required, e.g.in eczema, psoriasis. 23

ADVANTAGES

4) The hydrophobicity and retention of pharmaceutical ointments are useful attributeswhenever applied to mucosa, e.g. İnflamed haemorrhoids, eyelids, where fluidflow/inflammation at these sites would normally serve to remove otherformulations (e.g. oil in water creams) by dilution. It should be noted, however, thatspreading of ointments on to moist surfaces may be difficult due to thehydrophobic properties of most ointments.

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DISADVANTAGES

1) Pharmaceutical ointments are generally greasy and difficult to remove (and aretherefore often cosmetically unacceptable). Similarly, liniments and lotions mayalso be cosmetically unacceptable to the patient and difficult to use .

2) Pharmaceutical pastes are generally applied as a thick layer at the required site andare therefore considered to be cosmetically unacceptable.

3) Staining of clothes is often associated with the use of pharmaceutical pastes andointments

4) The viscosity of pharmaceutical ointments, and in particular pastes, may beproblematic in ensuring spreading of the dosage form over the affected site.Conversely, the low viscosity of liniments and lotions may result in applicationdifficulties

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DISADVANTAGES

5) Pharmaceutical ointments may not be applied to exuding sites however, pleasenote that this does not hold for pastes .Liniments may not be applied to brokenskin.

6) Problems concerning drug release from pharmaceutical ointments may occur if thedrug has limited solubility in the ointment base.

7) Pharmaceutical pastes are generally not applied to the hair due to difficultiesassociated with removal.

8) Therapeutic agents that are prone to hydrolysis should not be formulated intoaqueous gels.

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The formulation of ointments and pastes involves the dispersal or dissolution of theselected therapeutic agent into an ointment base and, therefore, in addition to thephysical properties of the dispersed/dissolved drug, the physicochemical properties ofthe ointment base are fundamental to the clinical and non-clinical performance of thistype of dosage form. The choice of ointment base is dependent on several factors,including: (1) the site of application; (2) the required rate of drug release; (3) thechemical stability of the drug; and (4) the effect of the therapeutic agent onformulation viscosity.

TYPES OF BASE

There are four types of base that are used to

formulate pharmaceutical

ointments and pastes: (1) hydrocarbon; (2)

absorption; (3) watermiscible/removable

; and (4) water-soluble.

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(1) HYDROCARBON BASES

❖ Hydrocarbon bases (oleaginous bases) are water-free, and

aqueous preparations may be incorporated into them only in small

amounts and then with difficulty.

❖ Hydrocarbon bases are retained on the skin for prolonged periods,

do not permit the escape of moisture from the skin to the

atmosphere, and are difficult to wash off.

❖ As such they act as occlusive dressings. They do not "dry out" or

change noticeably upon aging.

• Petrolatum

❑ a mixture of semisolid hydrocarbons

obtained from petroleum

❑ an unctuous mass, varying in color

from yellow to white

❑ It may be used alone or in

combination with other agents as an

ointment base

❑ Commercial product is Vaseline

•Paraffin

▪A purified mixture of solid hydrocarbons

obtained from petroleum.

▪A colorless or white, more or less translucent

mass that may be used to harden or stiffen

oleaginous semisolid ointment bases.

Liquid paraffin

a colorless, odorless oily liquid consistingof a mixture of hydrocarbons obtainedfrom petroleum

has the same character with paraffin

be used in combination with paraffin toadjust viscosity

•Hydrophilic Petrolatum

▪ is composed of cholesterol, stearyl alcohol, white wax, and white

petrolatum

▪has the ability to absorb water, with the formation of a water-in-oil

emulsion.

▪Aquaphor is a highly refined variation of Hydrophilic Petrolatum and

because it can absorb up to 3 times its weight in water, it has proven

useful to incorporate extemporaneously a water-soluble drug into

an oleaginous base.

▪may contain no more than 0.25% of water.

▪ insoluble in water, but mixes without

separation with about twice its weight of

water

▪The incorporation of water results in the

formation of a water-in-oil emulsion.

Anhydrous Lanolin (refined wool fat)

▪ a semisolid, fatlike substance obtained from

the wool of sheep.

▪ a water-in-oil emulsion that contains between

25 and 30% water.

▪ Additional water may be incorporated into

lanolin by mixing.

Lanolin (hydrous Wool Fat )

• Beeswax and spermaceti

▪ They are weak sufactants (W/O) and used as stabilization

agents in O/W emulsive ointment.

MINERAL OIL

a mixture of liquid hydrocarbons.

It is useful as a levigating substance to

wet and to incorporate solid substances

into the preparation of ointments that

consist of oleaginous bases as their

vehicle.

Absorption bases may be of two types:

those that permit the incorporation of aqueous solutions, resulting in the

formation of water-in-oil emulsions (e.g. Hydrophilic Petrolatum and

Anhydrous lanolin) and those that are already water-in-oil emulsions

(emulsion bases) that permit the incorporation of small, additional

quantities of aqueous solutions (e.g. lanolin and Cold Cream).

2) ABSORPTION BASES

▪These bases are useful as emollients although they do not

provide the degree of occlusion afforded by the oleaginous

bases.

▪Absorption bases are not easily removed from the skin with

water washing.

▪They are also useful pharmaceutically to incorporate aqueous

solutions of drugs, e g., sodium sulfacetamide, into oleaginous

bases.

❑ oil-in-water emulsions that are capable of being washed from skin or

clothing with water. For this reason, they are frequently referred to as

"water-washable" ointment bases

❑may be diluted with water or with aqueous solutions.

❑ have the ability to absorb serous discharges in dermatologic conditions.

❑Certain medicinal agents may be better absorbed by the skin when

present in a base of this type than in other types of bases.

3)WATER-REMOVABLE BASES

•Emulsifying agents

➢sodium lauryl sulfate :O/W emulsion

➢stearyl alcohol and cetyl alcohol representing the oleaginous phase of

the W/O emulsion to improve the stabilization and viscosity.

➢ sodium stearate and calcium stearate.

➢Glyceryl monostearate: weak W/O emulsifying agents and used as

stabilization agents and emollient in the O/W emulsion.

Stearic acid, beewax and paraffin are the main oleaginous

bases.

propylene glycol and water representing the aqueous phase

Methylparaben and propylparaben are used to preserve the

ointment against microbial growth

• contain only water-soluble components.

• are water washable

•Because they soften greatly with the addition of water, aqueous

solutions are not effectively incorporated into these bases. Rather, they

are better used for the incorporation of nonaqueous or solid substances.

4) WATER-SOLUBLE BASES

SELECTION OF THE APPROPRIATE BASE

1. Desired release rate of the drug substance from the ointment base

2. Desirability of topical or percutaneous drug absorption

3. Desirability of occlusion of moisture from the stability of the drug in the ointment base

4. Effect, if any, of the drug on the consistency or other features of the ointment base

5. Desire for a base easily removed by washing with water

6. Characteristics of the surface to which it is applied for example, an ointment is generally applied to dry, scaly skin; a cream is applied to weeping or oozing surfaces; and a lotion is applied to intertriginous areas or where friction may occur, as between the thighs or under the armpit.

The base that provides the best combination of the most desired attributes should be selected. 44

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Semisolid production machine with heat jacketed vessel, high - shear mixer,scrapper, vacuum attachments, and control station

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