Quality control of suspensions

A number of procedures have been suggested in the past for evaluating the physical stability of suspensions. Some of these are empirical in the sense that they have no mathematical base. Some methods currently being used are so drastic that they destroy the structure of the suspension. The methods used may be categorized as:

(a) Sedimentation methods:

 Since formation of the sediment and its redispersibility are two features related to the overall acceptability of suspensions, many evaluation procedures centre around sedimentation properties.

The simplest procedure for evaluation is to keep a measured volume of the suspension in a graduated cylinder in an undisturbed state for a certain period of time and note the volume of the sediment, which is expressed as ultimate height (hu). This, in relation to the initial volume of the suspension, (Ho) is expressed as sedimentation ratio. It should, however, be noted that sedimentation ratio (hu/Ho) is dependent on time and it is likely to vary at different periods of time. The sedimentation ratios at different periods of time can be plotted against time abscissa to give a curve that indicates the sedimentation pattern on storage. If the curve is horizontal to time axis it indicates a better suspension. However, if it steeps down it indicates a poor formulation. Sometimes it may be useful to dilute original suspension to known extents before determination of sedimentation ratios.

(b) Rheological methods:

 Evaluation of rheological behaviour of the suspension can help in predicting the settling pattern and can also provide clues to vehicle particle structure. In carrying out rheological study of a suspension generally low shear rates are employed and samples are evaluated undisturbed. By use of a Brookfield viscometer with T-spindle the rheological reatures at different depths in a sample can be studies. Data collected on samples stored for various periods of time can give useful information about the stability of the suspension.

(c) Electrokinetic methods:

 As has been discussed in the chapter on emulsions, the surface electric charge or zeta potential is instrumental in deciding the stability of disperse phase systems. Certain zeta potentials produce more stable suspension because of controlled flocculation. Hence, determination of zeta potential of a suspension can give valuable clues to its stability. The migration velocities of particles can be measured by electrophoretic methods and zeta potential calculated from it.

(d) Micromeritic methods: 

In the ultimate, the stability of a suspension is inter-related to the size of particles constituting its disperse phase. A growth in the particle size is a pointer towards its instability since such an occurrence can ultimately result in the formation of lumps or cake destroying the physical structure of a suspension and rendering it useless. Hence, an appreciation of change in particle size with passage of time can provide an insight into the stability aspect of a suspension. Changes in absolute particle size, particle size distribution, crystal habit etc. can be worked out by microscopy, coulter counter etc.

Quality control of emulsions

Evaluation is a necessary step in any formula development since it enables the development scientist to know whether his product possess the projected qualities or not. In biphasic products like emulsions the stability of physical structure is of paramount significance. The following evaluatory tests are usually done on the emulsions.

(a) Phase separation :

The rate and degree of phase separation in an emulsion can be easily determined by keeping a certain amount in a graduated cylinder and measuring the volume of separated phase after definite time intervals. The phase separation may result from creaming or coalescence of globules and these possibilities should be kept in mind.

Coalescence is a definite sign of instability and it generally becomes apparent within a month in instable formulations. The phase separation test can be accelerated by centrifugation at low/moderate speeds. One can at best expect a mixture of creamed and coalesced particles and in such a situation it may be difficult to make correct interpretations. High speed centrifugation (2,00,000 g) can be used to test the strength of interfacial films. At such speeds poor emulsions would crack up completely while only those with tough interfacial films may survive.

(b) Globule size :

Growth in the globule size after the preparation of an emulsion is an indication of its physical instability. Hence, size of globules and their size distribution is generally ascertained in an emulsion over a certain time span. In the beginning there generally occurs some change in the size but it may be due to inadequate surface coverage of globules by surfactants. Thereafter in a good formulation the globule size gets stabilized. If the globule size continues to grow it is indicative of a poor product which may get completely disorganized with time. The globule size is measured by microscopic methods or by electronic devices such as coulter counters. In either of these two techniques the original product has to be suitably diluted before estimations. This may introduce errors because of incomplete deflocculation or new patterns of flocculation in diluted emulsions. Hence, while making a judgement about the stability of the emulsion this aspect should be kept in mind.

(c) Flow properties: 

The rheological characteristics of an emulsion system depend upon globule size, emulsifier and its concentration, phase volume ratio etc., and hence determination of its flow characteristics could serve as an index of its stability. Therefore study of flow behavior of an emulsion is an integral part of its evaluation. Since most emulsions have non-Newtonion flow results may tend to differ if only one point viscosity measurements are made. Many emulsions exist in a flocculated state and disturbance caused due to measurements results in structure which may be contributing to their consistency. Use of a heliapath attachment with Brookfield viscometer helps in detection of creaming tendency and hence it is advisable to study rheological properties over extended periods of time can help in prediction of their long-term behaviors. Many emulsions show change in consistency with time which follows linear relationship when plotted on a log-log scale over a number of ten fold time intervals.

(d) Effect of thermal stresses: 

It is usual to evaluate the stability of an emulsion by subjecting it to high and low temperature in alternating cycles. The samples are first exposed to 60°C for a few hours and then to 0 to 4°C. Such exposures are repeated a number of times and emulsion stability assessed after each cycle. Such thermal stresses are in fact hard treatments and emulsions that survive them can be deemed to be really robust. It is to be noted that these thermal stresses cannot be directly correlated to actual shelf life situations. However, the extremes of temperatures may influence partitioning of the emulgent between the two phases or cause melting or crystallization of some fatty components and this gives an indirect clue to emulsion stability. The effect of thermal stresses on different emulsions do not follow any set pattern and vary from formulation to formulation. It has also not been possible to compute emulsion stability at room temperatures from its behavior at high temperatures. This evaluation has its significance in the fact that no formulator can possibly wait for years to evaluate shelf life of his product and hence he subjects the same to magnified artificial stresses in order to get some feel about structure stability. He may in this process accumulate valuable data which ultimately enables him to differentiate between “good” and “bad” products.

Quality control of capsules

The evaluation of capsules, in general, follows the line for compressed tablets and tests like the weight variations test, content uniformity test, disintegration and dissolution time.

Weight variation : 

This test is done by taking 20 capsules individually, determining average weight per capsule and finding out weight variation of each capsule against the average value(± 10% variations are permitted). However, if the variations are beyond this limit net weight of contents of each capsule should be determined, and compared with average net weight. This will remove any doubt about the possible variation in the weights of individual shells. As per standards specified in some Pharmacopoeias net weight of not more than two capsules should differ by more than ± 10% from the average net weight and no capsule should differ by more than ± 25%. If the average net weights of 2 to 6 capsules deviate by ± 10 to 25%, net weights of 40 more capsules should be determined. In a total of 60 capsules not more than six should deviate from average by more than ± 10% and none by more than ±25%.

Disintegration and dissolution time :

 Capsules are not normally tested for disintegration as their shells are known to dissolve rapidly in the gastric fluids. However, capsules which are designed to be enteric, by treatment of their shells with formaldehyde, should be tested thus to ensure than they do not disintegrate in simulated gastric juice under simulated conditions. Dissolution time tests are run on the lines of compressed tablets. Any of the standard apparatus available for dissolution tests can be employed. The determination of dissolution time is important since absorption of drugs depends upon their dissolution times.

Drug content uniformity :

 In solid dosage forms uniform distribution of medicaments remains a problem. The problem becomes more acute with potent medicaments administered in low doses. Hence, a number of capsules should be selected and assayed for drug content individually. Pharmacopoeias specify 30 capsules out of which 10 should be assayed individually in the first instance. Out of these at least 9 should be within ±15% of average and none should be beyond ±25. If 1 to 3 capsules out of the 10 assayed originally fall outside ±15% the remaining 20 should be assayed. Out of the total 30 capsules at least 27 should be within ±15% and no capsule should be beyond ±25%.

Quality control of tablets

Tablets may be evaluated for their physical characteristics, drug contents, dissolution sites, rate of release of drug etc. Certain physical properties of drugs like uniformity of weight, hardness, friability, thickness, disintegration and dissolution times are important characteristics having a bearing on their handling and use.

(1) Weight Uniformity:

It is desirable that every individual tablet in a batch is uniform in weight, and the weight variation, if any, is within the permissible limits (generally ± 5% for tablets weighing more than 325 mg). Non-uniformity in weights can lead to variation in dosaging. Hence, all finished bathes of tablets should be sampled and tested for weight uniformity. Generally 20 tablets are weighed collectively and individually. From the collective weight average weight per tablet is calculated. The weights of individual tablets are then compared with the average weight to ascertain whether the variations in weights are within permissible limits or not. Some of the basic causes of weight variation of tablets are faulty incorporation of glidants and resultant poor flow of granules, wide variations in granule sizes, differences in lower punch length, improper lubricants etc.

(2) Hardness :

hardness of a tablet is indicative of its tensile strength and is measured in terms of load/pressure required to crush it when placed on its edge. A number of handy hardness testers such as, Mosanto type or Pfizer type are currently in use. A tablet hardness of about 5 kg is considered to be minimum for uncoated tablets for mechanical stability. The hardness is a function of physical properties of granules like their hardness and deformation under load, binders and above all the compressional force. The hardness has influence on disintegration and dissolution times and is as such a factor that may affect bioavailabilities.

(3) Thickness :

The thickness of a tablet depends mainly upon die filling, physical properties of materials to be compressed and compressional forces. There is bound to be a small variation in the thicknesses of individual tablets in a batch but it should be of such an order that it does not immediately become apparent to unaided eye. The thickness can be easily measured by micrometers or in holding trays with sliding caliper scale. Thickness should not vary beyond ± 5% of the standard value.

(4) Friability :

Friability generally refers to loss in weight of tablets in the containers due to removal of fine particles from their surfaces. However, in wider sense chipping and fragmentations can also be included in friability. Friability generally reflects poor cohesion o tablet ingredients. Standard devices have been fabricated to measure friabilities. Generally such instruments, marketed as `Friability Test Apparatus’ or `Friabilators’, consist of a circular plastic chamber, divided into 2-3 compartments. The chamber rotates at a speed of 25 r.p.m. and drops the tablets by a distance of 15 cms. Preweighed tablets are placed in the apparatus which is given 100 revolutions after which the tablets are weighed once again. The difference in the two weights represents friability. The weight loss should not be more than one percent.

SEMI-SOLID DOSAGE FORM:

DEFINITION:

Semi solids are the topical dosage form used for the therapeutic, protective or cosmetic function. They may be applied to the skin, or used nasally, vaginally, or rectally.

IDEAL PROPERTIES OF SEMISOLID DOSAGE FORMS :

PHYSICAL PROPERTIES

• ·         Smooth texture
• ·         Elegant in appearance
• ·         Non dehydrating
• ·         Non gritty
• ·         Non greasy and non staining
• ·         Non hygroscopic

PHYSIOLOGICAL PROPERTIES

• ·        Non irritating
• ·        Do not alter membrane / skin functioning
• ·         Miscible with skin secretion
• ·     Have low sensitization index

APPLICATION PROPERTIES

• ·     Easily applicable with efficient drug release.
• ·     High aqueous washability.

ADVANTAGES:

Avoid of first pass metabolism. Site specific action of drug on affected area. Convenient for unconscious patient or patient having difficulty on oral administration. Suitable dosage form for bitter drugs. More stable than liquid dosage form.

DISADVANTAGES:

May cause staining. They are bulky to handle. Application with finger may cause contamination. Physico-chemically less stable than solid dosage form. May cause irritation. Allergic to some patients.

CLASSIFICATION:

1. ·         creams
2. ·         poultice
3. ·         gels
4. ·         pastes
5. ·         ointments
6. ·         suppositories
7. ·         plasters non-sterile sterile

OINTMENTS

Homogeneous, translucent, viscous, semi-solid preparation, most commonly a greasy, thick oil (oil 80% - water 20%) with a high viscosity, Applied to the skin or mucous membranes.

Uses Emollients application of active ingredients to the skin Occlusive

CREAMS

Viscous semisolid emulsion system with opaque appearance as contrasted with translucent ointments.

Consistency depends on weather the cream is w/o or o/w. W/O creams O\W creams Contains lipophilic emulsifying agent.

Used as emollient and as cleansing agent.

Contains O\ W emulsifying agent.

 O/W creams are elegant drug delivery system.

PASTES

Contains high percentage of insoluble solid (usually 50 % or more)

Pastes are usually prepared by incorporating solids directly into a congealed system by levigation with a portion of the base to form a paste like mass.

They have good adhesion on skin and less greasy.

GELS AND JELLIES

Gels and jellies are semisolid system in which a liquid phase is constrained within a 3-D polymeric matrix having a high degree of physical or chemical cross-linking. Gels are aqueous colloidal suspensions of the hydrated forms of insoluble medicament. Jellies are transparent or translucent non-greasy semisolid and contains more water than gels. Used for medication, lubrication and carrier for spermicidal agents to be used intra vaginally with diaphragms.

POULTICES (CATAPLASMS)

They are wet masses of solid matter applied to the skin in order to reduce inflammation and in some cases to act as a counter-irritant. Poultice must retain heat for a considerable time. After heating the preparation is spread on dressing and applied to the affected area. E.g. Kaolin poultice (B.P.C.)

PLASTERS

Plasters are solid or semisolid masses made by incorporating medicaments in resinous or waxy bases which are melted and spread on suitable backing material they are mainly used to, Afford protection and mechanical support. Furnish an occlusive and macerating action. Bring medication into close contact with the surface of the skin.

SUPPOSITORIES

It is solid or stiffened semisolid dosage form intended for insertion into body orifices where they melt, soften, or dissolve and exert local or systemic effects.

TYPES

(1)  Rectal suppositories

(2)  Pessaries

(3)  Urethral bougies

(4)  Nasal bougies

(5)  Ear cones

FORMULATION OF SEMISOLID DOSAGE FORMS :

INGREDIENTS USED IN PREPARATION OF SEMISOLIDS

(1)  Active pharmaceutical ingredient (API)

(2)  Bases

(3)  Preservative

(4)  Humectants

(5)  Antioxidants

(6)  Emulsifier

(7)  Gelling agent

(8)  Permeation enhancer

(9)  Buffers

1. BASES:

It is one of the most important ingredient used in formulation of semisolid dosage form. Ointment and suppository bases do not merely act as the carriers of the medicaments, but they also control the extent of absorption of medicaments incorporated in them. 16

IDEAL PROPERTIES OF A BASE:

They should be, Inert, non-irritating and non-sensitizing. Compatible with skin pH and the drug. Good solvent and/or emulsifying agent. Emollient, protective, non-greasy and easily removable. Release medicament readily at the site of application. Pharmaceutically elegant and possess good stability.

TYPES OF BASES:

A.      Oleaginous bases.

B.      Absorption bases.

C.      Emulsion bases.

D.     Water soluble bases.

A) Oleaginous (hydrocarbon) bases. :

They consist of a combination of more than one oleaginous material such as water-insoluble hydrophobic oils and fats. They are highly compatible; occlusive; good emollients. They are anhydrous, do not absorb water, readily (hydrophobic) insoluble in water, not washable. Examples: Vaseline, hard paraffin, liquid paraffin, white ointment.

Uses: protectants, emollient, and vehicle for solid drugs.

B) Absorption (Emulsifiable) Bases :

Have capacity to absorb considerable quantities of water or aqueous solution and turn to w/o without marked changes in consistency. They are anhydrous, water insoluble and water unwashable. They have good emollient but poor occlusive property.

Uses: protectants, emollient, and vehicle for aqueous solutions and solid drug.

C) Emulsion Bases :

According to the type of emulsion, these bases are classified as either W/O or O/W.

Uses: Cleansing creams, emollients and vehicle for solid and liquid drugs.

Emulsion Ointment Base (W/O):

·         Hydrous

·         Will absorb water

·         Insoluble in water

·         Not washable

·         Water-Oil-Emulsion

Emulsion Ointment Base (O/W):

·         Hydrous

·         Will absorb water

·         Insoluble in water

·         Washable

·         Oil-in-Water Emulsion

·         Hydrophilic Ointment

D) Water Soluble Bases :

These include both anhydrous and hydrous dermatological non-emulsion bases which are water soluble and contain no oil phase. Water soluble, water washable, greaseless. Because they soften with the addition of water, large amounts of aqueous solutions are not effectively incorporated into these bases. Examples . Carbowax compounds such as the polyethylene glycol bases containing pectin, cellulose, Bentonite, and gelatin.

2. PRESERVATIVE:

Some base, although, resist microbial attack but because of their high water content, it require an antimicrobial preservative. Commonly used preservatives include Methyl hydroxybenzoate Propyl hydroxybenzoate Chlorocresol Benzoic acid Phenyl mercuric nitrate

3. ANTIOXIDANTS :

Oxygen is a highly reactive atom that is capable of becoming part of potentially damaging molecules commonly called “free radicals.” Free radicals are capable of attacking the healthy cells of the body, causing them to lose their structure and function. To prevent this an antioxidants are added. E.g. Butylated hydroxy anisole, Butylated hydroxy toluene.

4. GELLING AGENTS :

Gelling agents, forms a gel, dissolving in the liquid phase as a colloid mixture that forms a weakly cohesive internal structure. These are organic hydrocolloids or hydrophilic inorganic substances.

 E.g. Tragacanth, Sodium Alginate, Pectin, Starch, Gelatin, Cellulose Derivatives, Carbomer, and Poly Vinyl Alcohol Clays.

 Material % Brookfield viscosity ‘CP 0’ Carbomer 941resin NF Carbomer 941resin NF Guar gum Methyl cellulose Sodium alginate 0.15 0.25 1.50 2.00 2.50 2900 6300 8040 5200 10400

5. PERMEATION ENHANCERS :

Skin can act as a barrier. With the introduction of various penetration enhancers, penetration of the drug through the skin can be improved. Sr. no Permeation enhancer Drugs used

1. Menthol, carvacrol, linalool Propranolol hydrochloride

2. Limonene Indomethacin, ketoprofen

3. Geraniol, nerolidol Diclofenac sodium

4. Oleic acid Piroxicam

6. EMULSIFIER :

An emulsifier (emulgent) is a substance that stabilizes an emulsion by increasing its kinetic stability. One class of emulsifiers is known as surface active substances, or surfactants. Ideal properties of emulsifier includes,

a) Must reduce surface tension for proper emulsification.

b) Prevents coalescence and should quickly absorb around the dispersed phase.

c) Ability to increase the viscosity at low concentration.

d) Effective at low concentration

7. HUMECTANT:

A humectant is a hygroscopic substance. It is often a molecule with several hydrophilic groups, most often hydroxyl groups. Since hygroscopic substances absorb water from the air, they are frequently used in desiccation or for humidity buffering.

Humectants are used to :

·         increase the solubility of the active ingredient.

·         to elevate its skin penetration.

·         the hydration of the skin.

8. BUFFERS:

Buffers are added for various purpose such as : Compatibility with skin. Drug solubility. Drug stability. Influence ionization of drug. Skin, due to its weak acidic nature, tolerates weak acidic preparations. E.g. sodium acetate, sodium citrate, potassium metaphosphate.

9. VEHICLE:

Purified water, water for injection, Water for injection may be used in ophthalmic semi solid preparations like eye ointment, gels etc.

METHODS OF PREPARATION:

A. TRITURATION

This method is also known as levigation, incorporation or mechanical mixing. When base contain soft fats and oils or medicament is solid and insoluble or liquid, then this method is use.

B. FUSION

This method is used :-

 When soft fats or waxes are to be incorporated with hard fats or waxes then of this to be melted to get homogenous mixture with stirring.

Solid drugs that are readily soluble in melted base.

C. CHEMICAL REACTIONS

In chemical method a new product is formed by chemical reaction, which involves both fusion and mechanical mixing. Best example of such method is Iodine ointment. E.g. Ointment containing free iodine Iodine is only slightly soluble in most fats and oils. Iodine is readily soluble in concentrated solution of potassium iodide due to the formation of molecular complexes KI.I 2 , KI.2I 2 , KI.3I 2 etc. These solutions may be incorporated in absorption-type ointment bases. 38

EVALUATION OF SEMI SOLID DOSAGE FORM:

(1)  Physical methods

Test of rate of absorption

Test of non-irritancy

Test of rate of penetration

Test of rate of drug release

Test of rheological properties

Test of content uniformity

(2)  Microbiological methods

Test of microbial content

Test of preservative efficacy

PHYSICAL METHODS:

1.TEST OF RATE OF ABSORPTION

The ointment should be applied over a definite area of the skin by rubbing. At regular intervals of time, serum and urine samples should be analyzed for the quantity of drug absorbed.

2. TEST OF NON-IRRITANCY

Non-irritancy of the preparation is evaluated by patch test. In this test 24 human volunteers are selected. Definite quantity of ointment is applied under occlusion daily on the back or volar forearm for 21 days. Daily the type of pharmacological action observed is noted. No visible reaction or erythema or intense erythema with edema and vesicular erosion should occur. A good ointment base shows no visible reaction.

3. TEST OF RATE OF PENETRATION

Flow-through diffusion cell or microdialysis method is used. Animal or human skin of definite area should be collected and tied to the holder present in a diffusion cell. The diffusion cell is placed in a fluid bath. Measured quantity of the preparation is applied over the skin and the amount of drug passed into the fluid is measured at regular intervals by analyzing the aliquots of fluid using a spectrophotometer.

4. TEST OF RATE OF DRUG RELEASE

A clean test tube is taken and the internal surface is coated with the preparation as a thin layer. Saline or serum is poured into the test tube. After a certain period of time, the saline is analyzed for the quantity of the drug. The amount of drug when divided by the time period gives the rate of drug release.

5. TEST OF RHEOLOGICAL PROPERTIES

The viscosity of the preparation should be such that the product can be easily removed from the container and easily applied to the skin. Using cone and plate viscometer the viscosity of the preparation is determined.

MICROBIOLOGICAL METHODS:

1. TEST OF MICROBIAL CONTENT

Solutions of different samples of the preparation are made. Each sample is inoculated into separate volumes of 0.5 ml of rabbit's plasma under aseptic conditions and incubated at 37 0 C for 1-4 hours. No formation of the clot in the incubated mass indicates the absence of the micro-organisms.

2. TEST OF PRESERVATIVE EFFICACY

Using pour plate technique the number of micro-organisms initially present in the preparation are determined. Solutions of different samples of the preparation are made and mixed with Tryptone Azolectin (TAT) broth separately. All cultures of the micro-organisms are added into each mixture, under aseptic conditions. All mixtures are incubated. The number of micro-organisms in each sample are counted on 7th, 14th, 21st and 28th days of inoculation.

REFERENCES:

Cooper and Gunn’s ; Dispensing for Pharmaceutical Students; 12 th edition; CBS publishers and distributors Pvt. Ltd; 192-229. Atamaram Pawar and R.S. Gaud; Modern Dispensing Pharmacy; 1 st edition; Career Publications; 199-232. Leon Lachman, Herbert A. Lieberman, Joseph H. kanig; The Theory and Practice of Industrial Pharmacy; 3 rd edition; Varghese publication; 534-563. Dr. A.K. Seth; Pharmaceutics-II (Dispensing and Formulation); S. Vikas and Co. Publishing house; 262-319. http://www.pharmainfo.net/free-books/novel-semisolid-dosage-forms http://www.pharmainfo.net/evaluation-ointments

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Related reading:

• Quality control of Suppositories
• Quality control of Ointments
• Displacement value 

Quality Control of Suppositories

Each manufactured batch of suppositories must be tested to ascertain whether the required standards are met or not. A visual examination must be carried out for general appearance and suppositories carrying medicaments in suspension should be sliced longitudinally to determine uniform disposition of the medicament.

Assay of the therapeutically active ingredients is also a must to establish whether each unit carries labeled amounts of the drugs or not.

The other necessary tests are the following:

(a)  Determination of the melting range

(b)  Determination of the disintegration/dissolution times

(c)   Fragility assessment

(d)  Drug uptake rates

Determination of the melting range

The melting range determination presents no problem since many melting range devices with high degree of precision are available. This test is necessary only for hydrophobic base suppositories.

Determination of the disintegration/dissolution times

The disintegration and dissolution times can be determined by use of the equipment available for these tests on compressed tablets, with necessary modifications in the test media. Suppositories with water soluble bases are subjected to these tests.

Fragility assessment

Fragility is tested to determine the tensile strength of the suppository to assess whether it will be able to withstand the rigors of normal handling or not.

Drug uptake rates    

Many suppositories carry medicaments for local action and there is no need to carry out drug uptake tests on them. However, those carrying medicaments fro systemic action should necessarily be subjected to in vitro and in vivo tests for drug uptake.

In the in vitro tests the conditions of the test must simulate the situations obtaining in the body cavity. 

Quality Control of Ointments

Generally ointments are evaluated for the following qualities:

(1) Penetration: 

For assessing the penetration some vary simple experiments have been suggested. Weighed quantities of the ointments are rubbed over definite areas of the skin for a given length of time. Thereafter the unabsorbed ointment is collected from the skin and weighed. The difference between the two weights roughly represents the amount absorbed.

(2) Rate of release of medicaments: 

To assess rate of release of a medicament small amount of the ointment can be placed on the surface of nutrient agar contained in a Petri dish or alternately in a small cup cut in the agar surface. If the medicament is bactericidal the agar plate is previously seeded with a suitable organism like S. aureus. After a suitable period of incubation the zone of inhibition is measured and correlated with the rate of release. The rate of release of salicylic acid is ascertained by incorporating an iron salt in the agar and measuring the colored zone around the spot where ointment was applied.

(3) Absorption of medicaments into blood stream: 

The diadermatic ointments should be evaluated for the rate of absorption of drug into the blood stream. This test can be run in vivo only. Definite amounts of ointments should be rubbed through the skin under standard conditions and medicaments estimated in the blood plasma or urine.

(4) Irritant effect: 

In general no ointment should possess irritant effect on the skin or mucous membranes. The tests for irritancy can be carried out on the skin and eyes of rabbits or the skin of human beings. The irritant effect can also be judged to a certain extent by injecting the ointment into thigh muscles and under the abdominal skin in rats. Reactions are noted at intervals of 24, 48, 72 and 96 hours. Lesions on cornea, iris, conjuctiva are used for judging the irritancy to the eyes. Presence of patches on the skin within 2 weeks indicate irritancy to skin.

Drug Incompatibility

Drug Incompatibility Pharmaceutical incompatibility of a drug refers to interactions between two or more substances which lead to changes in chemical, physical and therapeutic properties of the drug or its dosage form.
Incompatibility occurs as a result of mixing of two or more “Antagonistic Substances” & an undesirable product is formed which may affect the safety, efficacy & appearance of the pharmaceutical preparation.

Incompatibilities are usually unintentional.

It may occur in vitro between drugs & other components during preparation, storage or administration.

Types of Drug Incompatibility

There are three types of drug incompatibilities-

1. Therapeutic incompatibility

2. Physical incompatibility

3. Chemical incompatibility

Therapeutic Incompatibility

It is the modification of the therapeutic effect of one drug due to the prior concomitant administration of another, or it may occur due to overdose or wrong dose of the drug being prescribed. Basically the interaction can alter the pharmacokinetic or pharmacodynamic property of the drug.

Pharmacokinetics interactions involve alteration of absorption, distribution, metabolism and excretion of the drug 

Pharmacodynamics interactions involve modulation of pharmacological response resulting in synergistic, antagonistic, potentiation or additive response. This can also lead to altered cellular drug transport.

Examples:

1. Tetracycline interacts with milk forming unabsorbed complex (altered absorption).

2. Antibiotics kill large number of normal flora of intestine, thus drugs like digoxin when given with antibiotics, toxicity appears due to altered metabolism of digoxin.

3. Sulphonamide displaces warfarin thus leading to bleeding (altered distribution).

4. Penicillin and tetracycline are weak acid and are unionized in acidic pH thus are reabsorbed in the body (altered excretion)

5. Caffeine oral increases and chloral hydrate oral decreases sedation and drowsiness, thus two should not be prescribed together.

Physical Incompatibility

Physical incompatibility is the result of interaction between two or more substances which lead to change in color, odor, taste, viscosity and morphology. It can occur due to insolubility of prescribed agent in vehicle, immiscibility of two or more liquids or liquification of solids mixed in a dry state (called eutexia). The solubility of the drug can be altered due to change in pH, milling, use of surfactant, chemical reaction, complex formation and co-solvent used.

Examples:

1. Benzalkonium chloride and sodium lauryl sulfate when are mixed, a precipitate is formed because benzalkonium chloride is positive charged while sodium lauryl sulfate has negative charge.

2. A prescription containing Ephedrine sulfate, menthol and liquid paraffin is incompatible due to ephedrine sulphate , a salt soluble in water not in organic solvents, oil and paraffin.

Immiscibility appears in emulsion, creams, lotions and ointments In can happen due to incomplete mixing, addition of surfactants, presence of microorganism or change in temperature. Liquefaction, a physical incompatibility occurs when two solid substances are mixed together, conversion to a liquid state takes place.

The reasons for liquefaction are

(i) When the solid substance is soluble in another solid substance, decrease of its melting point and conversion to a liquid take place.

(ii) By mixing hydrated crystals and dry crystals, crystalline water diffuses to dry crystals leading to formation of liquid.

Chemical Incompatibility

Chemical incompatibility is a reaction between two or more substances which lead to change in chemical properties of drug or its pharmaceutical dosage form. It can occur due to oxidation, hydrolysis, polymerization, isomerization, decarboxylation, absorption of CO2, combination or formation of insoluble complexes.

Chemical incompatibility is of two types:

Tolerated Chemical Incompatbility: 

The incompatability is minimized by changing the order of mixing not the components.

Adjusted Chemical Incompatability:

Here addition or substitution of interacting component is done without affecting the efficacy. In sodium salicylate mixture, syrup of lemon is used as flavorant, it reacts with sodium salicylate, forming an insoluble salicylic acid, thus instead of syrup of lemon, tincture of lemon can be used.

Some other examples of such type of incompatibility include:

Examples:

1. Phenylephrine shows change in color due to oxidation.

2. Penicillin G sodium is affected by acidic condition created syrup of cherry and thus an indiffusible penicillinoic acid is formed which is an inactive product.

3. Potassium chlorate-tannic acid formulation is explosive, therefore minimal rubbing is required 4. Sodium bicarbonate-borax-glycerin preparation leads to evolution of carbon dioxide, therefore formulation must be dispensed once the gas is ceased down.

Intentional Incompatibilities

Intentional incompatibilities are observed in some prescriptions, which are done to modify the activity of one in presence of other.

Examples:

1. Atropine and morphine prescribed together, the former should antagonize the depressant effect of morphine to the respiratory tract.

2. A mild laxative antacid such as Mg(OH)2 may be used to overcome the constipating effect of an astringent antacid such as AL(OH)3.

3. Tincture myrh is diluted with water to give a precipitate which is used as a gargle in the treatment of tonsillitis.

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