The Biphasic Dosage form : Suspensions

Definition

• A suspension is biphasic system in which a dispersed state is solid while continuous phase is liquid (oily/aqueous), the system is stabilized by addition of “Suspending agent.”
• Most pharmaceutical suspensions are aqueous in nature.

Advantages

• Suspensions offer distinct advantages they are as follows:

1. Stability:

• Some drugs are not stable in solution form.
• In such cases it is necessary to prepare an insoluble form of that drug.
• Therefore drugs are administered in the form of suspension.
• e.g. Procaine Penicillin G.

2. Choice of solvent:

• If the drug is not soluble in water and solvents other than water are not acceptable, suspension is the only choice.
• e.g. Parenteral corticosteroid.

3. Mask the taste;

• In some cases drugs are made insoluble and dispensed in the form of suspension to mask the objectionable taste.
• e.g. Chloramphenicol base is very bitter in taste, hence the insoluble chloramphenicol palmitate is used which does not have the bitter taste

4. Prolonged action:

• Suspension has a sustaining effect, because, before absorption the solid particles should be dissolved.
• This takes some time. e.g. Protamine Zinc Insulin and Procaine Penicillin G.

5. Bioavailability:

• Drugs in suspension exhibit a higher bioavailability compared to other dosage forms (except solution) due to its large surface area, higher dissolution rate.
• e.g. Antacid suspensions provides immediate relief from hyperacidity than its tablet chewable tablet form.

Types of suspensions

• The pharmaceutical suspension preparations are differentiated into suspensions, mixtures, magmas, gels and lotions.

Suspensions

• Simple suspension is the insoluble solid dispersed in a liquid.
• The stability considerations suggest that the manufacture of drugs in dry form is ideal.
• They are reconstituted as suspensions using a suitable vehicle before administration.

Few examples are:
i) Dispersible tablets of antibiotic, Amoxicillin (e.g. NovaMOX)
ii) Procaine penicillin G powder (E.G. PENIDURE)

Gels

• Gels are semisolid systems consisting of small inorganic particles suspended in a liquid medium.
• It consists of a network of small discrete particles.
• It is a two-phase system.
• e.g. Aluminum hydroxide gel.

Lotions

• Lotions are suspensions which are intended to be applied to the unbroken skin without friction.
• e.g. Calamine lotion, Hydrocortisone lotion.

Magmas and Milks

• Magmas and milk are aqueous suspensions of insoluble, inorganic drugs and differ from gels mainly in that the suspended particles are larger.
• When prepared they are thick and viscous and because of this, there is no need to add a suspending agent.
• e.g. Bentonite magma, Milk of Magnesia.

Mixtures

• Mixtures are oral liquids containing one or more active ingredients, dissolved, suspended or dispersed in a suitable vehicle.
• Suspended solids may separate slowly on standing, but are easily redispersed on shaking.
• e.g. Kaolin mixture with pectin.

Classification of suspensions

• Based on the proportion of solids, suspensions are empirically classified as dilute or concentrated systems.

i) Dilute suspensions :

• Solid content 2 - 10 % e.g. Cortisone acetate and Prednisolone acetate suspension.

ii) Concentrated suspensions

• Solid content 10 - 50 % e.g. Zinc oxide suspension for external use, Procaine penicillin G injection, Antacid suspension etc.

Depending on the nature and behavior of solids, suspensions are classified as flocculated and deflocculated.

Deflocculated suspension

• In this system, solids are present as individual particles.

Flocculated suspension

• In this system, particles aggregate themselves by physical bridging.
• These flocs are light, fluffy conglomerate which are held together by weak van der Waal’s forces of attraction.
• The difference between Flocculated and Deflocculated Suspensions is as follows,

Deflocculated System

Flocculated System

i)        Pleasant appearance, because of uniform dispersion of particles. ii)      Supernatant remains cloudy. iii)    Particles exist as separate entities iv)    Rate of sedimentation is slow, as the size of particles are small. v)      Particles settle independently and separately vi)    The sedimentation is closely packed and form a hard cake. vii)  The hard cake cannot be redispersed. viii)Bioavailability is higher due to large specific surface area.

i)        Somewhat unsightly sediment. ii)      Supernatant is clear iii)    Particles form loose aggregates. iv)    Rate is high, as flocs are the collection of smaller particles having a larger size. v)      Particles settle as flocs. vi)    Sediment is a loosely packed network and hard cake cannot form. vii)  The sediment is easy to redisperse. viii)Bioavailability is comparatively less due to small specific surface area.

Factors affecting the stability of a suspension:

• Settling in suspensions

Brownian movement:

• Brownian movement of particles prevents sedimentation.
• In general, particles are not in a state of Brownian motion in pharmaceutical suspensions, due to,

i) larger particle size (Brownian movement is seen in particles having diameter of about 2 to 5 mm (depending on the density of the particles and the viscosity and the density of the suspending medium.
ii) and higher viscosity of the medium.

Sedimentation:

• The rate of sedimentation of particles can be expressed by the Stoke’s law, using the following formula:

Where ,
d is the particle diameter
P_s, P_l are densities of a particle and liquid respectively.
g is the acceleration of gravity.
n is the viscosity of the medium.

• Stock’s law is applicable if:

i) particles are spherical; but particles in the suspension are largely irregular.
ii) Particles settle freely and independently.

• In suspensions containing 0.5 - 2 % (w/v) solid, the particles do not interfere with each other during sedimentation - hence free settling occurs.
• Most pharmaceutical suspensions contain 5 - 10 % or higher percentages of solid. in this cases particles interfere with one another as they fall - hence hindered settling occurs and Stoke’s law no longer applies.
• Stoke’s law is applicable to deflocculated systems, because particles settle independently.
• However, this law is useful in a qualitative manner in fixing factors which can be utilized in formulation of suspensions.

1. Particle size:

• Rate of sedimentation is directly proportional to “(diameter of particle)^2”
• So smaller the particle size more stable the suspension.
• The particle-particle interaction results in the formation of floccules or coagules where the sedimentation rate increases.
• The particles are made fine either by dry milling prior to suspension or wet-milling of the final suspension in a colloid mill or a homogenizer.

2. Viscosity of the medium

• According to Stoke’s law:
• Rate of sedimentation is inversely proportional to the viscosity of medium.
• Viscosity of the suspension should be optimum.
• Viscosity can be increased by adding suspending agents or thickening agents.
• Selection of high viscosity have both advantages and disadvantages.

Advantages
i) Sedimentation rate is retarded, hence enhances the physical stability of the suspension.
ii) Inhibits crystal growth, because movement of particles is diminished.
iii) Prevents the transformation of metastable crystals to stable crystals.
Disadvantages
i) Redispersibility of the suspension on shaking is difficult.
ii) Pouring out of the suspension from the container may be difficult.
iii) Creates problems in the handling of materials during manufacture.
iv) May retard absorption of drugs from the suspension.

3. Density:

• Rate of sedimentation is directly proportional to the differences of densities of solids and liquids. (density of solid - density of liquid medium).
• Lesser the difference between the densities of solid particles and liquid medium slower is the rate of sedimentation.
• Since it is very difficult to change the absolute density of the solid particles so the density of the liquid medium can be manipulated by changing the composition of the medium.
• The addition of nonionic substances such as sorbitol, polyvinylpyrrolidone (PVP), glycerin, sugar, or one of the polyethyleneglycols or combination of these may be helpful in the manipulation.
• If the density of the particles is greater than the continuous medium the particles will settle downwards, the phenomenon is known as sedimentation.
• If the density of particle is lesser than that of the liquid medium then the particles will move upward - the phenomenon is known as creaming.

Formulation of suspensions:

• The product must,

1) Flow readily from the container
2) Possesses a uniform distribution of particles in each dose.

• Two approaches are commonly employed to secure the two requirements,

(i) The use of structured vehicle to maintain deflocculated particles in suspension.

• Structured vehicles are pseudoplastic and plastic in nature; it is frequently desirable that thixotropy be associated with these two type of flow.
• Structured vehicles act by entrapping the particles so that, ideally no settling occurs.
• In reality some degree of sedimentation will usually take place.
• The shear thinning property of these vehicle does however facilitate the redispersion when shear is applied.

(ii) Application of the principles of flocculation to produce flocs that, although, they settle rapidly are easily redispersed with a minimum of agitation.

Preparation of suspensions

• Method of preparations can be subdivided into two broad categories:

1) Precipitation method:

• There are three methods

1. organic solvent precipitation
2. precipitation effected by changing the pH of the medium and
3. double decomposition
(i) Organic solvent precipitation:

• Water insoluble drugs can be precipitated by dissolving them in water-miscible organic solvents (e.g. alcohol, acetone, propylene glycol and polyethylene glycol) and then adding the organic phase to distilled water under standard conditions produces a suspension having a particle size in the 1 to 5 mm range.
• Example: Prednisolone is precipitated from a methanolic solution to produce a suspension in water.
• Disadvantage: Harmful organic solvents may be difficult to remove.
• Advantage: In case of parenteral or inhalation therapy very fine particles are required, which can be prepared by this method.

(ii) Precipitation effected by changing the pH of the medium:

• A drug may be readily soluble at a certain pH and precipitate at another pH.
• This type of drug is first dissolved in the favorable pH and then the solution is poured in another buffer system to change the pH of the medium and the drug will form a suspension in the medium of the second pH.
• Example 1: Estradiol suspensions can be prepared by changing the pH of the of its aqueous solution; estradiol is readily soluble in alkali as potassium or sodium hydroxide solutions. If a concentrated solution of estradiol is thus prepared and added to a weakly acidic solution of hydrochloric, citric or acetic acids, under proper conditions of agitation, the estradiol is precipitated in a fine state of subdivision.
• Example 2: Insulin suspension may also be prepared by pH change method. Insulin has an isoelectric point of approximately pH5. When it is mixed with a basic protein, such as protamine, it is readily precipitated when pH is between the isoelectric points of the two components, i.e. pH 6.9 to 7.3. Protamine-Zinc-Insulin (PZI) contains an excessive quantity of zinc to retard the rate of absorption. According to the British Pharmacopoeia phosphate buffer is added to an acidified solution of PZI so that the pH is between 6.9 to 7.3 to form the suspension.

(iii) Double decomposition method

• In this method two water soluble reagent forms a water insoluble product.
• Example: White Lotion NF is prepared by slowly adding zinc sulfate solution in a solution of sulphurated potash to form a precipitate of zinc polysulphide.

2) Dispersion method:

• In this cases the powder form of the drug is directly dispersed in the liquid medium.
• The liquid medium should have good power of wetting the powder.

1. Small scale preparation method:

• A suspension is prepared on the small scale by grinding or levigating the insoluble material in the mortar to a smooth paste with a vehicle containing the dispersion stabilizer and gradually adding the remainder of the liquid phase in which any soluble drugs may be dissolved.
• The slurry is transferred to a graduate, the mortar is rinsed with successive portions of the dispersion medium is finally brought to the final volume.

2. Large scale preparation method:

• On large scale dispersion method the solid particles are suspended using ball, pebble and colloid mills.
• Dough mixers, pony mixers and similar apparatus are also employed.

Evaluation of Suspension Stability:

• Prepared suspensions are evaluated by using following criterias,

1. Sedimentation Volume.
2. Degree of Flocculation.
3. Redispersibility.
4. Rehologic Methods.
5. Particle Size Changes.

Chemistry of AntiTubercular Drugs

What is Tuberculosis?

• Tuberculosis is an infectious disease caused due to bacteria of Mycobacterium species e.g.

1. Mycobacterium tuberculosis. (Humans).
2. Mycobacterium bovis. (animals).
3. Mycobacterium avium complex. (Extra pulmonary tuberculosis).

• Usually tuberculosis affects respiratory system as it spreads through air.
• It attacks apex part of lungs and starts to grow there causing necrosis of affected area.
• The affected area is called as “tubercle” becomes radio-opaque during X-Ray examinations.
• Due to caused infection, the destructed alveoli tissues shows inflammation and cause irritation leading to cough (most common symptom) followed with hyperpyrexia.

What are symptoms of Tuberculosis?

1. Persistent cough for three or more weeks.
2. Hyperpyrexia at evening which disappears at night following profuse sweating.
3. Blood in sputum.
4. Excessive phlegm production.
5. Weakness with chest pain.
6. Weight loss.

Diagnosis of Tuberculosis:

1. Monteux Test.
2. Sputum Test.
3. chest X-Ray examination.

Why Tuberculosis bacteria is tough to treat and produce resistance to most of available drugs?

• The Mycobacterium tuberculosis has a specific cell wall which contains very high amount of lipids and hence resists alcohols, alkalies, acids and even some disinfectants, which helps it to spread.
• The bacteria produces necrosis in surrounding area making entry of blood closed in affected area.
• The bacteria grows very slowly.
• The bacteria not only survives but also grows even when swallowed by WBCs.

Treatment of Tuberculosis:

Antitubercular Drugs:

• The drugs which are used in treatment of tuberculosis are called as antitubercular drugs.
• As tuberculosis bacteria is infamous for producing drug resistance the treatment is usually given in combination of drugs avoiding use of single drug.
• The drugs used in the treatment are classified on the basis of their toxicity as first line drugs, second line of drugs and third line drugs.

First Line Drugs:

1. Isoniazid.
2. Ethambutol..
3. Pyrazinamide.
4. Streptomycin.
5. Rifampicin.

Second line Drugs:

1. Para Amino Salicylic Acid.
2. Cycloserine.
3. Kanamycin.
4. Amikacin.
5. levofloxacin

Third line Drugs:

1. Clarithromycin.
2. Rifabutin.
3. Linezolide.

Classification of Antitubercular Drugs Based on Chemical Structure:

1. Salicylic Acid Derivative:

• e.g. Para Amino Salicylic Acid.

1. Pyridine Derivatives:

• Isoniazid.
• Ethionamide.
• Prothionamide.

1. Pyrazine Derivative:

• Pyrazinamide.

1. Ehtylenediaminobutanol Derivatives.

• Ethambutol..

1. Antibiotics:

• Streptomycin.
• Rifampicin.
• Kanamycin.

1. Miscellaneous:

• Fluroquinolones : Moxifloxacin, Levofloxacin.
• Macrolides: Sparfloxacin.
• Tetracyclines: Minocycline

Isoniazid:

• It is a first line compound used in treatment of tuberculosis.
• It is also known as INH, Isonicotinic acid hydrazide.
• 
• This drug is a simple pyridine derivative.

Mechanism of action:

• Isoniazid is in fact a “prodrug” as after bacterial metabolism it gets converted to active compounds like,

1. Isonicotinicaldehyde.
2. Isonicotinic acid.
3. Isonicotinamide.

• It is supposed to act by interfering with functions of bacterial enzymes.
• However, its main mechanism of action is supposed to be the “Mycolic acid” synthesis inhibition.
• Mycolic acid is one of the major ingredients of the mycobacterial cell wall, inhibiting its synthesis INH makes the Mycobacterium vulnerable causing its death.

SAR of Isoniazid:

• 
• The N1 in hydrazine side chain is essential for action and hence should not be substituted.
• The N2 can be substituted with alkyl compounds to get active products.
• The Pyridine ring is found essential for activity, substitution results into loss of activity.
• Many analogues which were developed are not found superior to the parent drug.
• However, the R2 replacement with isopropyl group resulted in formation of a new drug “Iproniazid” possessing “psychomotor  stimulant activity.

Metabolism & Excretion:

• Isoniazid is get metabolized by “acetylation”.
• It get excreted freely in urine.

Adverse Effects:

1. Neuritis.
2. Hepatotoxicity.
3. Anorexia.
4. vomiting.
5. Nephrotoxicity.

Dose:

• 50mg to 300mg daily in combination with other antitubercular drugs.
• Maximum allowed dose is 900mg/day.
• Vit. B6 (Pyridoxine) is usually given with INH to reduce neuritis.

Ethambutol.

• Ethambutol is abbreviated as “E” or “EMB”.
• It is a water soluble bacteriostatic drug which shows a great absorption when taken orally (80%).
• 
• Chemically it is a aliphatic diamine with two butanol sidechains.

SAR of Ethambutol:

• Presence of two amino moieties is essential for action.
• Presence of branched alkyl groups on the nitrogens of amino group also influences the activity.
• Addition of heteroatom to ethylene moiety diminishes the activity.
• Replacement of alcoholic –OH groups with –OCH3 (methoxy) or –OC2H5 (ethoxy) groups produced equipotent compounds.

Mechanism of Action:

• Ethambutol works by interfering with cell wall formation of Mycobacterium and hence produce bacteriostatic action in multiplying bacterias.

“Mycolic acid is one of the main constituent of mycobacterial cell wall, Ethambutol prevents formation of “Mycolyl-Arabinogalactan-Peptidoglycan” complex.
By preventing synthesis of arabinogalactan from arabinosyl transferase.”

Metabolism:

• Metabolism of Ethambutol takes place in liver and 75% of the drug gets excreted unchanged.

Adverse / Toxic Effect:

1. Optic Neuritis.
2. Nausea.
3. Anorexia.
4. Hyperuricaemia.

Therapeutic uses:

1. In treatment of pulmonary and extra pulmonary tuberculosis.
2. As first line drug in treatment of Tb.

Rifampicin.

• Rifampicin is an antibiotic belonging to the class “Macrocyclic Antibiotics: Rifamycins”.
• They were obtained from soil bacterium “Streptomyces mediterranei”.
• Total “7” rifamycins being isolated as Rifamycin A,B,C,D,E,S,SV.
• Rifampicin is semisynthetic derivative of Rifamycin B.

Mechanism of Action: 

• Rifampicin inhibits bacterial “DNA dependent RNA polymerase” enzyme causing inhibition of RNA synthesis and in turn inhibition of protein synthesis.
• Rifampicin is highly effective is its MIC (Minimum Inhibitory Concentration) is just 0.005 to 0.2 microgram per ml.

SAR of Rifampicin:

• Rifampicin is a semisynthetic analogue of “Rifamycin-B” obtained by adding “[(4-methyl-1-piperazinyl)imino)methyl]” at 3^rd  carbon.
• The presence of flat naphthalene ring is essential for antibacterial action.
• Presence of –OH groups and double bonds are essential for action.
• Intact macrocyclic ring is essential for action.
• Presence of carbonyl group is also found essential for action.
• Its a zwitterion and having good lipid as well as water solubility.

Therapeutic Uses:

1. As first line therapy in treatment of Tuberculosis in combination with other drugs.
2. Also used in treatment of Leprosy.
3. Along with Doxycycline it is used to treat Brucellosis.
4. In prophylaxis of  H. meningitides.

Side effects/ Adverse effects:

1. Change in urine color.
2. Hyperbilirubinaemia.
3. Thrombocytopenia.
4. Hepatotoxicity.
5. Rashes.

Pyrazinamide

• It is a “Pyrazine” derivative classified in first line drugs for treatment of Tuberculosis.
• It gets converted to its active form inside the bacteria and produces its action.

Mechanism of Action:

• Exact mechanism of action is yet not known.
• It gets converted to “pyrazinoic acid” in bacteria which is its active form.
• It is known to disrupt bacterial cell membrane and transport mechanisms.

SAR of Pyrazinamide:

1. The replacement of pyrazine ring with any other ring diminishes the activity.
2. The monosubstituted ring is essential as di substituted rings found to have lesser activity, however, after introduction of QSAR to di substituted derivatives were introduced which were found to have activity.

Therapeutic uses:

1. It is used in treatment of Tuberculosis and classified as first line of drugs.
2. It is used in combination with INH and rifampicin in cases where resistance is suspected.

Side effects / Adverse effects:

1. Hepatotoxicity.
2. Hyperuricaemia.
3. Arthralgia.
4. GI upset.

Streptomycin.

• It is an aminoglycoside antibiotic.
• It is obtained from a soil bacteria “Streptomyceus  greseus”.

Mechanism of Action:

• Streptomycin irreversibly inhibits bacterial protein synthesis and is bactericidal.
• Streptomycin binds with 30S unit of bacterial ribosome and causes inhibition of bacterial synthesis in the following ways,

1. Interferes with initiation complex of peptide formation.
2. Misreading of mRNA which leads to formation of nonfunctioning or toxic proteins.
3. Breaking of Polysomes into nonfunctional monosomes.

Uses of Streptomycin:

1. As first line drug in treatment of Tuberculosis in combination with other drugs.
2. In treatment of septicemia in combination with penicillin or metronidazole.
3. In treatment of tularemia and plague.
4. In treatment of streptococcal infections along with penicllins.

Side effects/ Adverse effects:

1. Hepatotoxicity.
2. Nephrotoxicity.
3. Ototoxicity.
4. GI upset.

Note:

• Although it is used with penicillins many times both drugs must not be mixed physically as they cause neutralization of each others activity.

CoTrimoxazole

CoTrimoxazole is a rational combination of two antifolate drugs,

1. Pyrimidine Analogue : Trimethoprim.
2. Sulfonamide: Sulfamethoxazole.

used in treatment of various diseases where alone drug fails.

• CoTrimoxazole name itself indicates “ COmbination of TRIMethoprim and SulfamethOXAZOLE”.
• This combinations offers “Synergistic Effect” hence the benefit is more than used alone.

Mechanism of Action:

• These drugs attack the bacterial folic acid synthesis pathway at different steps and prevent bacterial folic acid synthesis leading to a “Bactericidal Effect”.
• Sulfamethoxazole inhibits bacterial enzyme “Folate Synthtase”  and prevents formation of “Dihydrofolic acid from PABA (Para Amino Benzoic Acid).
• Trimethoprim inhibits bacterial enzyme “Dihydrofolate Reductase” and prevents conversion of “Dihydrofolic acid to Tetrahydrofolic acid.”.

Dose Combination:

• This is a fixed dose combination that comes in 1:5 ratio of Trimethoprim and Sulfamethoxazole i.e. 80 mg of Trimethoprim is combined with 400 mg of Sulfamethoxazole.
• Double dose DS combination combines 160 mg of Trimethoprim and 800 mg of Sulfamethoxazole.
• Lower dose or half dose combines 40 mg of Trimethoprim and 200 mg of Sulfamethoxazole.

Benefits of CoTrimoxazole:

• Produces synergistic effect “Two drugs acting at different sites to produce similar response.”
• Spectrum of antimicrobial activity is greater than that of sulfonamide alone
• Development of resistance is slow.

Why CoTrimoxazole is a rational combination?

• Both drugs have similar activity i.e Antibacterial.
• Half lives of both drugs are almost similar i.e. Sulfamethoxazole 10 Hrs and Trimethoprim 8 Hrs.
• They have different mechanism of action but similar pharmacokinetic profiles.

Pharmacokinetics of CoTrimoxazole

Component	Tmax (h)	Vd (L)	Protein binding	t1/2 (h)	Excretion
Sulfamethoxazole	1-4	20	66%	8-10	Renal
Trimethoprim	1-4	130	42-45%	10	Renal

Uses:

1. Urinary tract infection
2. Respiratory tract infection
3. Bacterial dysentery
4. Skin infections & burns.
5. Malaria
6. Travelers diarrhea.

Adverse Effects:

1. Crystaluria – causing kidney damage
2. Kernicterus(Bilirubin induced brain dysfunction) in foetus & neonates
3. Hypersensitivity reaction and skin rashes
4. Aplastic anaemia
5. Steven Johnson’s syndrome (SJS)

Contraindications:

1. Known hypersensitivity.
2. Pregnancy.
3. Neonates bellow 6 weeks.
4. Hepatic failure.
5. Renal Failure.

Market Brands:

1. Bactrim.
2. Septran.

Note:

• Combination of Trimethoprim and Sulfadiazine is called as “CoTrimazine”

Semisolid Dosage Forms: Ointments.

Definition: Ointments are semisolid preparations for application to the skin or mucosae.

• The ointment bases are almost always anhydrous and generally contains one or more medicaments in suspension or solution.

Characteristics of an ideal ointment:

1.       It should be chemically and physically stable.

2.       It should be smooth and free from grittiness.

3.       It should melt or soften at body temperature and be easily applied.

4.       The base should be non-irritant and should have no therapeutic action.

5.       The medicament should be finely divided and uniformly distributed throughout the base.

Classification of ointments

According to their therapeutic properties based on penetration of skin.

 (a) Epidermic, (b) Endodermic, (c) Diadermic

(a) Epidermic ointments

These ointments are intended to produce their action on the surface of the skin and produce local effect.

They are not absorbed.

They acts as protectives, antiseptics and parasiticides.

(b) Endodermic ointments

These ointments are intended to release the medicaments that penetrate into the skin. They are partially absorbed and acts as emollients, stimulants and local irritants.

(c) Diadermic ointments

These ointments are intended to release the medicaments that pass through the skin and produce systemic effects.

OINTMENT BASES

The ointment base is that substance or part of an ointment preparation which serves as carrier or vehicle for the medicament.

An ideal ointment base should be inert, stable, smooth, compatible with the skin, non-irritating and should release the incorporated medicaments readily.

Classification of ointment bases:

1.       Oleaginous bases

2.       Absorption bases

3.       Water-miscible bases

4.       Water soluble bases

OLEAGINOUS BASES

These bases consists of oils and fats. The most important are the

Hydrocarbons i.e. petrolatum, paraffins and mineral oils.

The animal fat includes lard.

The combination of these materials can produce a product of desired melting point and viscosity.

(a) Petrolatum (Soft paraffin)

This is a purified mixture of semi-solid hydrocarbons obtained from petroleum or heavy lubricating oil.

Yellow soft paraffin (Petrolatum; Petroleum jelly)

This a purified mixture of semisolid hydrocarbons obtained from petroleum. It may contain suitable stabilizers like, antioxidants e.g. a-tocopherol (Vitamin E), butylated hydroxy toluene (BHT) etc.

Melting range : 38 to 56⁰C.

White soft paraffin (White petroleum jelly, White petrolatum)

This a purified mixture of semisolid hydrocarbons obtained from petroleum, and wholly or partially decolorized by percolating the yellow soft paraffin through freshly burned bone black or adsorptive clays.

Melting range : 38 to 56⁰C.

Use: The white form is used when the medicament is colourless, white or a pastel shade. This base is used in

Dithranol ointment B.P.

Ammoniated Mercury and Coal tar ointment B.P.C.

Zinc ointment B.P.C.

(b) Hard paraffin (Paraffin)

This is a mixture of solid hydrocarbons obtained from petroleum.

It is colourless or white, odorless, translucent, wax-like substance. It solidifies between 50 and 57⁰C and is used to stiffen ointment bases.

(c) Liquid paraffin (Liquid petrolatum,; White mineral oil)

It is a mixture of liquid , hydrocarbons obtained from petroleum. It is transparent, colourless, odourless, viscous liquid.

On long storage it may oxidize to produce peroxides and therefore, it may contain tocopherol or BHT as antioxidants.

It is used along with hard paraffin and soft paraffin to get a desired consistency of the ointment. Tubes for eye, rectal and nasal ointments have nozzles with narrow orifices through which it is difficult to expel very viscous ointments without the risk of bursting the tube. To facilitate the extrusion upto 25% of the base may be replaced by liquid paraffins.

Advantages of hydrocarbons bases:

(i)      They are not absorbed by the skin. They remain on the surface as an occlusive layer that restricts the loss of moisture hence, keeps the skin soft.

(ii)    They are sticky hence ensures prolonged contact between skin and medicament.

(iii)  They are almost inert. They consist largely of saturated hydrocarbons, therefore, very few incompatibilities and little tendency of rancidity are there.

(iv)   They can withstand heat sterilization, hence, sterile ophthalmic ointments can be prepared with it.

(v)    They are readily available and cheap.

Disadvantages of hydrocarbon bases;

(i)      It may lead to water logging followed by maceration of the skin if applied for a prolonged period.

(ii)    It retains body heat, which may produce an uncomfortable feeling of warmth.

(iii)  They are immiscible with water; as a result rubbing onto the surface and removal after treatment both are difficult.

(iv)   they are sticky, hence makes application unpleasant and leads to contamination of clothes.

(v)    Water absorption capacity is very low, hence, these bases are poor in absorbing exudate from moist lesions.

ABSORPTION BASE

The term absorption base is used to denote the water absorbing or emulsifying property of these bases and not to describe their action on the skin.

These bases (some times called emulsifiable ointment bases) are generally anhydrous substances which have the property of absorbing (emulsifying) considerable quantity of water yet retaining its ointment-like consistency.

                Preparations of this type do not contain water as a component of their basic formula but if water is incorporated a W/O emulsion results.

Wool Fat (anhydrous lanolin)

It is the purified anhydrous fat like substance obtained from the wool of sheep.

·         It is practically insoluble in water but can absorb water upto 50% of its own weight. Therefore it is used in ointments the proportion of water or aqueous liquids to be incorporated in hydrocarbon base is too large.

·         Due to its sticky nature it is not used alone but is used along with other bases in the preparation of a number of ointments.

e.g. Simple ointment B.P. contains 5% and the B.P. eye ointment base contains 10% woolfat.

Hydrous Wool Fat (Lanolin)

·         It is a mixture of 70 % w/w wool fat and 30 % w/w purified water. It is a w/o emulsion. Aqueous liquids can be emulsified with it.

·         It is used alone as an emollient.

·         Example:- Hydrous Wool Fat Ointment B.P.C., Calamine Coal Tar Ointment.

Wool Alcohol

It is the emulsifying fraction of  wool fat. Wool alcohol is obtained from wool fat by treating it with alkali and separating the fraction containing cholesterol and other alcohols. It contains not less than 30% of cholesterol.

Use:-  

·         It is used as an emulsifying agent for the preparation of w/o emulsions and is used to absorb water in ointment bases.

·         It is also used to improve the texture, stability and emollient properties of o/w emulsions.

Examples :- Wool alcohol ointment B.P. contains 6% wool alcohol and hard, liquid and soft paraffin.

Beeswax

It is purified wax, obtained from honey comb of bees.

It contains small amount of cholesterol. It is of two types: (a) yellow beeswax and (b) white beeswax.

Use:-

Beeswax is used as a stiffening agent in ointment preparations.

Examples:-Paraffin ointment B.P.C. contains beeswax.

Cholesterol

It is widely distributed in animal organisms. Wool fat is also used as a source of cholesterol.

Use:- It is used to increase the water absorbing power of an ointment base.

Example:- Hydrophilic petroleum U.S.P. contains:

                Cholesterol      3%

                Stearyl alcohol    3%

                White beeswax     8%

                White soft paraffin  86%

Advantages of absorption bases:

(i)       They are less occlusive nevertheless, are good emollient.

(ii)    They assist oil soluble medicaments to penetrate the skin.

(iii)  They are easier to spread.

(iv)   They are compatible with majority of the medicaments.

(v)    They are relatively heat stable.

(vi)   The base may be used in their anhydrous form or in emulsified form.

(vii) They can absorb a large quantity of water or aqueous substances.

Disadvantages: Inspite of their hydrophilic nature, absorption bases are difficult to wash.

WATER MISCIBLE BASES

They are miscible with an excess of water. Ointments made from water-miscible bases are easily removed after use.

There are three official anhydrous water-miscible ointment bases:-

Example:-            

EmulsifyingointmentB.P.                                                                - contains anionic emulsifier.

Cetrimide emulsifying ointment B.P.                                              - contains cationic emulsifier

Cetomacrogol emulsifying ointment B.P.                       - contains non-ionic emulsifier

Uses: they are used to prepare o/w creams and are easily removable ointment bases

e.g. Compound Benzoic Acid Ointment  (Whitfield’s Ointment) - used as antifungal ointment.

Advantages of water miscible bases:

(i)      Readily miscible with the exudates from lesions.

(ii)    Reduced interference with normal skin function.

(iii)  Good contact with the skin, because of their surfactant content.

(iv)   High cosmetic acceptability, hence there is less likelihood of the patients discontinuing treatment.

(v)    Easy removal from the hair.

WATER SOLUBLE BASES

Water soluble bases contain only the water soluble ingredients and not the fats or other greasy substances, hence, they are known as grease-less bases.

Water soluble bases consists of water  soluble ingredients such as polyethylene glycol polymers (PEG) which are popularly known as “carbowaxes” and commercially known as “macrogols”.

They are a range of compounds with the general formula:

                                                                CH₂OH . (CH₂OCH₂) _n CH₂OH

The PEGs are mixtures of polycondensation products of ethylene and water and they are described by numbers representing their average molecular weights. Like the paraffin hydrocarbons they vary in consistency from viscous liquids to waxy solids.

Example:-

                Macrogols 200, 300, 400                                   - viscous liquids

                Macrogols 1500                                                                   - greasy semi-solids

                Macrogols 1540, 3000, 4000, 6000                 - waxy solids.

Different PEGs are mixed to get an ointment of desired consistency.

Advantages of PEGs as ointment base:

(a)     They are water soluble; hence, very easily can be removed from the skin and readily miscible with tissue exudates.

(b)    Helps in good absorption by the skin.

(c)     Good solvent properties. Some water-soluble dermatological drugs, such as salicylic acid, sulfonamides, sulfur etc. are soluble in this bases.

(d)    Non-greasy.

(e)     They do not hydrolyze, rancidify or support microbial growth.

(f)      Compatibility with many dermatological medicaments.

Disadvantages:

(a)     Limited uptake of water. Macrogols dissolve when the proportion of water reaches about 5%.

(b)    Reduction in activity of certain antibacterial agents, e.g. phenols, hydroxybenzoates and quaternary compounds.

(c)     Solvent action on polyethylene and bakelite containers and closures.

Certain other substances which are used as water soluble ointment bases include tragacanth, gelatin, pectin, silica gel, sodium alginate, cellulose derivatives, etc.

FACTORS GOVERNING SELECTION OF AN IDEAL OINTMENT BASE

1. Dermatological factors

2. Pharmaceutical factors

1. Dermatological factors

(a) Absorption and Penetration:

‘Penetration’ means passage of the drug across the skin i.e. cutaneous penetration, and ‘absorption’ means passage of the drug into blood stream.

·         Medicaments which are both soluble in oil and water are most readily absorbed though the skin.

·         Whereas animal and vegetable fats and oils normally penetrate the skin.

·         Animals fats, e.g. lard and wool fat when combined with water, penetrates the skin.

·         o/w emulsion bases release the medicament more readily than greasy bases or w/o emulsion bases.

(b) Effect on the skin

·         Greasy bases interfere with normal skin functions i.e. heat radiation and sweating. They are irritant to the skin.

·         o/w emulsion bases and other water miscible bases produce a cooling effect due to the evaporation of water.

(c) Miscibility with skin secretion and sebum

Skin secretions are more readily miscible with emulsion bases than with greasy bases. Due to this the drug is more rapidly and completely released to the skin.

(d) Compatibility with skin secretions:

The bases used should be compatible with skin secretions and should have pH about 5.5 because the average skin pH is around 5.5. Generally neutral ointment bases are preferred.

(e) Non-irritant

All bases should be highly pure and bases specially for eye ointments should be non-irritant and free from foreign particle.

(f) Emollient properties

Dryness and brittleness of the skin causes discomfort to the skin therefore, the bases should keep the skin moist. For this purpose water and humectants such as glycerin, propylene glycol are used. Ointments should prevent rapid loss of moisture from the skin.

(g) Ease of application and removal

The ointment bases should be easily applicable as well as easily removable from the skin by simple washing with water. Stiff and sticky ointment bases require much force to spread on the skin and during rubbing newly formed tissues on the skin may be damaged.

2. Pharmaceutical factors

(a) Stability

Fats and oils obtained from animal and plant sources are prone to oxidation unless they are suitably preserved. Due to oxidation odour comes out. This type of reactions are called rancidification. Lard, from animal origin, rancidify rapidly. Soft paraffin, simple ointment and paraffin ointment are inert and stable. Liquid paraffin is also stable but after prolonged storage it gets oxidized. Therefore, an antioxidant like tocopherol (Vit -E) may be incorporated. Other antioxidants those may be used are butylated hydroxy toluene (BHT) or butylated hydroxy hydroxy anisole (BHA).

(b) Solvent properties

Most of the medicaments used in the preparation of ointments are insoluble in the ointment bases therefore, they are finely powdered and are distributed uniformly throughout the base.

(c) Emulsifying properties

Hydrocarbon bases absorbs very small amount of water.

Wool fat can take about 50% of water and when mixed with other fats can take up several times its own weight of aqueous solution.

Emulsifying ointment, cetrimide emulsifying ointment and cetomacrogol emulsifying ointment are capable of absorbing considerable amount of water, forming w/o creams.

(d) Consistency

The ointments produced should be of suitable consistency. They should neither be hard nor too soft. They should withstand climatic conditions. Thus in summer they should not become too soft and in winter not too hard to be difficult to remove from the container and spread on the skin.

The consistency of an ointment base can be controlled by varying the ratio of hard and liquid paraffin.

PREPARATION OF OINTMENTS

A well-made ointment is -

(a) Uniform throughout i.e. it contains no lumps of separated high melting point ingredients of the base, there is no tendency for liquid constituents to separate and insoluble powders are evenly dispersed.

(b) Free from grittiness, i.e. insoluble powders are finely subdivided and large lumps of particles are absent. Methods of preparation must satisfy this criteria.

Two mixing techniques are frequently used in making ointments:

1. Fusion, in which ingredients are melted together and stirred to ensure homogeneity.

2. Trituration, in which finely-subdivided insoluble medicaments are evenly distributed by grinding with a small amount of the base or one of its ingredients followed by dilution with gradually increasing amounts of the base.

1. Ointments prepared by Fusion method:

When an ointment base contain a number of solid ingredients such as white beeswax, cetyl alcohol, stearyl alcohol, stearic acid, hard paraffin, etc. as components of the base, it is required to melted them. The melting can be done in two methods:

Method-I

The components are melted in the decreasing order of their melting point i.e. the higher m.p. substance should be melted first, the substances with next melting point and so on. The medicament is added slowly in the melted ingredients and stirred thoroughly until the mass cools down and homogeneous product is formed.

Advantages:

This will avoid over-heating of substances having low melting point.

Method-II

All the components are taken in subdivided state and melted together.

Advantages:

The maximum temperature reached is lower than Method-I, and less time was taken possibly due to the solvent action of the lower melting point substances on the rest of the ingredients.

Cautions:

(i)      Melting time is shortened by grating waxy components (i.e. beeswax, wool alcohols, hard-paraffin, higher fatty alcohols and emulsifying waxes) by stirring during melting and by lowering the dish as far as possible into the water bath so that the maximum surface area is heated.

(ii)    The surface of some ingredients discolors due to oxidation e.g. wool fats and wool alcohols and this discolored layers should be removed before use.

(iii)  After melting, the ingredients should be stirred until the ointment is cool, taking care not to cause localized cooling, e.g. by using a cold spatula or stirrer, placing the dish on a cold surface (e.g. a plastic bench top) or transferring to a cold container before the ointment has fully set. If these precautions are ignored, hard lumps may separate.

(iv)   Vigorous-stirring, after the ointment has begun to thicken, causes excessive aeration and should be avoided.

(v)    Because of their greasy nature, many constituents of ointment bases pickup dirt during storage, which can be seen after melting. This is removed from the melt by allowing it to sediment and decanting the supernatant, or by passage through muslin supported by a warm strainer. In both instances the clarified liquid is collected in another hot basin.

(vi)   If the product is granular after cooling, due to separation of high m.p. constituents, it should be remelted, using the minimum of heat, and again stirred and cooled.

Example:

(i) Simple ointment B.P. contains

                                                                Wool fat                50g

                                                                Hard paraffin                       50g

                                                                Cetostearyl alcohol             50g

                                                                White soft paraffin             850g

Type of preparation:           Absorption ointment base

Procedure:

Hard paraffin and cetostearyl alcohol on water-bath. Wool fat and white soft paraffin are mixed and stirred until all the ingredients are melted. If required decanted or strained and stirred until cold and packed in suitable container.

(ii) Paraffin ointment base

Type of preparation:  Hydrocarbon ointment base

(iii) Wool alcohols ointment B.P.

Type of preparation: Absorption base

(iv) Emulsifying ointment B.P.

Type of preparation: Water-miscible ointment base.

(v) Macrogol ointment B.P.C

Type of preparation: Water soluble ointment base

Formula:               Macrogol 4000

                                Liquid Macrogol 300

Method: Macrogol 4000 is melted and previously warmed liquid macrogol 300 is added. Stirred until cool.

2. OINTMENT PREPARED BY TRITURATION

This method is applicable in the base or a liquid present in small amount.

(i)      Solids are finely powdered are passed through a sieve (# 250, # 180, #125).

(ii)    The powder is taken on an ointment-slab and triturated with a small amount of the base. A steel spatula with long, broad blade is used. To this additional quantities of the base are incorporated and triturated until the medicament is mixed with the base.

(iii)  Finally liquid ingredients are incorporated. To avoid loss from splashing, a small volume of liquid is poured into a depression in the ointment an thoroughly incorporated before more is added in the same way. Splashing is more easily controlled in a mortar than on a tile.

Example:

(i) Whitfield ointment (Compound benzoic acid ointment B.P.C.)

Formula:               Benzoic acid, in fine powder             6gm

                                Salicylic acid, in fine powder            3gm

                                Emulsifying ointment                         91gm

Method: Benzoic acid and salicylic acid are sieved through No. 180 sieves. They are mixed on the tile with small amount of base and levigated until smooth and dilute gradually.

(ii) Salicylic acid sulphur ointment B.P.C.

3. OINTMENT PREPARATION BY CHEMICAL REACTION

Chemical reactions were involved in the preparation of several famous ointments of the past, e.g. Strong Mercuric Nitrate Ointment, of the 1959 B.P.C.

(a) Ointment containing free iodine

Iodine is only slightly soluble in most fats and oils but readily soluble.

Iodine is readily soluble in concentrated solution of potassium iodide due to the formation of molecular complexes KI.I₂, KI.2I₂, KI.3I₂ etc.

These solutions may be incorporated in absorption-type ointment bases.

e.g. Strong Iodine Ointment B.Vet.C (British Veterinary Pharmacopoeia) is used to treat ringworm in cattle. It contains free iodine. At one time this type of ointments were used as counter-irritants in the treatment of human rheumatic diseases but they were not popular because:

They stain the skin a deep red color.

(i)      Due to improper storage the water dries up and the iodine crystals irritate the skin, hence glycerol was some times added to dissolve the iodine-potassium iodide complex instead of water.

Example: Strong Iodine Ointment B. Vet.C.

                                Iodine

                                Woolfat

                                Yellow soft paraffin

                                Potassium iodide

                                Water

Procedure:

(i)      KI is dissolved in water. I₂ is dissolved in it.

(ii)    Woolfat and yellow soft paraffin are melted together over water bath. Melted mass is cooled to about 40⁰C.

(iii)  I₂ solution is added to the melted mass in small quantities at a time with continuos stirring until a uniform mass is obtained.

(iv)   It is cooled to room temperature and packed.

Use: - Ringworm in cattle.

(b) Ointment containing combined iodine

Fixed oils and many vegetable and animal fats absorb iodine which combines with the double bonds of the unsaturated constituents, e.g.

CH₃.(CH₂) ₂.CH = CH.(CH₂) ₇.COOH + I₂ ® CH₃.(CH₂) ₂.CHI CHI.(CH₂) ₇.COOH

                                                Oleic acid                                                              di-iodostearic acid

Example: Non-staining Iodine Ointment B.P.C. 1968

                                Iodine

                                Arachis Oil

                                Yellow Soft Paraffin

Method:

(a)     Iodine is finely powdered in a glass mortar and required amount is added to the oil in a glass-stoppered conical flask and stirred well.

(b)    The oil is heated at 50⁰C in a water-bath and stirred continually. Heating is continued until the brown color is changed to greenish-black; this may take several hours.

(c)     From 0.1g of the preparation the amount of iodine is determined by B.P.C. method and the amount of soft paraffin base is calculated to give the product the required strength.

(d)    Soft paraffin is warmed to 40⁰C. The iodized oil is added and mixed well. No more heat is applied because this causes deposition of a resinous substance.

(e)     The preparation is packed in a warm, wide-mouthed, amber color, glass bottle. It is allowed to cool without further stirring.

4. PREPARATION OF OINTMENTS BY EMULSIFICATION

An emulsion system contain an oil phase, an aqueous phase and an emulsifying agent.

For o/w emulsion systems the following emulsifying agents are used:

                (i) water soluble soap

                (ii) cetyl alcohol

                (iii)glyceryl monostearate

                (iv) combination of emulsifiers: triethanolamine stearate + cetyl alcohol

                (v) non-ionic emulsifiers: glyceryl monostearate, glyceryl monooelate, propylene glycol stearate

For w/o emulsion creams the following emulsifiers are used:

                (i) polyvalent ions e.g  magnesium, calcium and aluminium are used.

                (ii) combination of emulsifiers: beeswax + divalent calcium ion

The viscosity of this type of creams prevent coalescence of the emulsified phases and helps in stabilizing the emulsion.

Example:

Cold cream:

Procedure:

(i)      Water immiscible components e.g. oils, fats, waxes are melted together over water bath (70⁰C).

(ii)    Aqueous solution of all heat stable, water soluble components are heated (70⁰C).

(iii)  Aqueous solution is slowly added to the melted bases with continuous stirring until the product cools down and a semi-solid mass is obtained.

N.B. The aqueous phase is heated otherwise high melting point fats and waxes will immediately solidify on addition of cold aqueous solution.