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 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.

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.