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INDUKAKA IPCOWALA COLLEGE OF PHARMACY  NEW V.V.NAGAR

PHYSICAL STABILITY

TESTING OF DOSAGE FORMS

Guided by: Sunil L. Baldania Dimal A. Shah

Prepared by: Shweta Singh 3rd Sem (P.A)

What is Physical Stability ?

Physical stability means that :• The formulation is totally unchanged through out its shelf-

life and has not suffered any changes by way of appearance, organoleptic properties, hardness, brittleness, particle size etc.

It affects :• Pharmaceutical elegance• Drug content uniformity• Drug release rate. 2

• The physical parameters associated with tablets are :

appearance hardness, softening, disintegration, dissolution, associated properties including slurry

pH.

TABLETS

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Appearance

• The general appearance of a tablet, its visual identity and overall ‘elegance’ is essential for consumer acceptance and lot- to- lot uniformity and general tablet- to- tablet uniformity, and for monitoring trouble free manufacturing.

• The control of general appearance involves the measurement of a number of tablet’s size, shape, colour, presence or absence of an odour, taste, surface texture, physical flaws and consistency, and legibility of any identifying markings.

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Tablet hardness

• The “hardness” of a tablet are usually assessed by subjecting the tablets to a diametral failure test.

• The tablet is placed (as shown in Figure) between two anvils, one of which is stationary. The other anvil is moved at constant speed against the tablet, and the force (as a function of time) is recorded.

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Tablets are made either by wet processing (wet granulation) or by dry processing (direct compression or slugging/roller compaction).

A binder in solution is added to the powder mixture, it forms soft bridges between particles, and when the granulation is dried then these bridges become hard.

During compression bond form between particles & the hardness of the tablet is tied in with the strength of the bond.

In order to form a bond, the particles or binder bridges must first be exposed to pressure that exceed the elastic limit of the material.

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• On failure, the material will either deform plastically or experience the brittle fracture.

• A material that flows well and has a low elastic limit is, therefore, easy to transform into a tablet, and several such materials, known as direct compression ingredients, are used in the manufacture of pharmaceutical tablets.

• In these cases drug is simply mixed with the direct compression excipient (and other excipients), lubricated, and compressed.

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• If the drug content is less than (approximately) 20% then the tablet will (generally) have the properties of the direct compression ingredient.

• At higher percentages, direct compression is usually only feasible if the drug substance itself is fairly compressible. (i.e., has a low elastic limit)

• The hardness of a tablet will be a function of the strength of the bond and the number of bonds.

• Hence it is the average bond density and the standard deviation of the bonds that are really of importance.

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Friability

• Tablets require a certain amount of resistance to friability, to withstand mechanical shock of handling in manufacture, packaging, and shipping.

• The lab friability tester is known as ROCHE FRIABILATOR.

• Pre-weighed tablets is placed in friabilator, which is then operated for 100 revolutions.

• The tablets are then dusted and reweighed.• Tablets that lose less than 0.5%-1.0% of their weight

are generally considered acceptable.

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Softening

• Softening can be associated with chemical interaction.

• Several furoic acids when tableted with microcrystalline cellulose, will cause a specific interaction leading to the formation of carbon monoxide (rather than decarboxylation of the acid).

• This interaction is not slow at 550c, and it causes the tablets to crumble. At room temperature the effect is less pronounced.

• Since a tablet, when produced, is not in equilibrium, there will be a redistribution of moisture.

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• This could make the bonds of a lower or a higher moisture content, and there may for this reason be a change in hardness during a fairly short period of time after manufacture.

• The moisture content of granules, when they are made initially, is a function of their particle size.

• When granules are dried, each is associated with one given drying time, t*.

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• Since the drying is a diffusional process, conventional diffusion theory predicts that the amount of moisture left in a granule m, in relation to the initial amount m0, is given to a first approximation where D is the diffusion coefficient of water in the granule and a is its diameter.

• The larger granules will have a higher moisture content at the beginning, but the moisture will equilibrate on storage.

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• It is of interest, in cases where moisture equilibrates and causes change in hardness on storage, to be able to assess the extent of moisture transfer within the tablet.

• However, Zoglio et al. (1975) have shown that in some cases (spray dried sucrose granules) there will be no redistribution of moisture between larger and smaller granules.

• In such cases (Shepky, 1974), the thermogravimetric method may be of advantage.

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Weight Variation

• With a tablet designed to contain a specific amount of drug in a specific amount of tablet formula, the weight of the tablet being made is routinely measured to help ensure that a tablet contain the proper amount of drug.

• The USP weight variation test is run by weighing 20 tablets individually, calculating the average weight, and comparing the individual tablet weight to the avarage.

• The tablet meet the test if NMT 2 tablets are outside the percentage limit and if no tablet differs by more than 2 times the percentage limit.

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Avg. wt. of tablet Maxx % diff. allowed

130 or less 10

130-324 7.5

More than 324 5

Disintegration

• Tablets (whether coated or not) are usually subjected to a disintegration test.

• The disintegration was the first in-vitro test used

by the U.S.P. It is now not obligatory compendially (but is recommended); it has been replaced by the dissolution test.

• Hence, it is the more important test, but it will be seen that there often is a correlation between the two, and since the disintegration test is much more easily carried out.

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• Disintegration of a tablet is a function of a several factors.

• If the tablet disintegrates by virtue of a disintegrant which expands, once it is wetted, then the most important attribute is the rate at which the disintegrating liquid penetrates the tablet, and hence the contact angle between the solid and the liquid is of importance.

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Dissolution

• The dissolution apparatuses usually used are USP type-1 (basket) or USP type-2 (paddle).

• Dissolution testing of pharmaceutical products is carried out for several different reasons.

• In the early stages, the intent of dissolution testing is to get a feel for comparative estimated bioavailability (on a rank order scale) of different formulations.

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• In preformulation, intrinsic dissolution rate constants are usually estimated.

• Although it is not possible, in a direct manner, to tie this in with an estimated bioavailability, it gives a feel for whether the drug substance will be exceedingly problematic, or (in rare cases) not problematic.

• This feel is comparative with the intrinsic

dissolution properties (obtained in a similar fashion) for other drug substances previously developed.

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Percolation Thresholds

• When a solid is compressed, then one might imagine that at ‘full’ compression, the tablet would be similar to a perfect crystal, in that there would be no void space left in it.

• This may be visualized as isolated pockets of void space or, as the porosity increases, strings of void, eventually terminating at the surface.

• The porosity at which latter situation is achieved is denoted the threshold value.

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• Threshold value for a drug & its excipients in combination are important because they govern such properties as dissolution, hardness & disintegration.

• In this concept, a cluster is defined as a group of nearest neighbour sites where all positions consist of the same component.

• There is a concentration where there is maximum probability that the cluster will start to percolate, & this is the percolation threshold.

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CAPSULES

Raw Materials for Capsules :

• The raw materials used in the manufacture of both hard and soft gelatin capsules are similar.

• Both contain gelatin, water, colorants and optional materials such as process aids and preservatives.

• soft gels are made up of gelatin, plasticizer, and materials that impart the desired appearance (colorants and/or opacifiers), and sometimes flavors. 21

1. Gelatin

• Gelatin is the major component of the capsules and has been the material from which they have traditionally been made.

• Gelatin has been the raw material of choice because of the ability of a solution to gel to form a solid at a temperature just above ambient temperate conditions, which enables a homogeneous film to be formed rapidly on a mould pin.

• Gelatin is a translucent brittle solid substance, colorless or slightly yellow, nearly tasteless and odorless, which is created by prolonged boiling of animal skin connective tissue or bones.

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• Type A gelatin is derived from an acid-treated precursor and exhibits an isoelectric point in the region of pH 9, whereas type B gelatin is from an alkali-treated precursor and has its isoelectric zone in the region of pH 4.7.

Physical properties of gelatin :

• Gelatin is a protein product produced by partial hydrolysis of collagen extracted from skin, bones, cartilage, ligaments, etc.

• Gelatin melts when heated and solidifies when cooled again. Together with water it forms a semi-solid colloidal gel.

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2. Colorants

• The colorants that can be used in capsules are of two types: water soluble dyes, or insoluble pigments or lakes.

• Colorants can be either synthetic or natural, and are used to impart the desired shell color for product identification.

• Three most commonly used dyes are erythrosine, indigo carmine and quinolone yellow.

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• The two types of pigments used are iron oxides- black, red and yellow and titanium dioxide which are white and used to make the capsule opaque.

• Interaction of dyes and gelatin in capsule shells, especially under light, could change the rate of drug release from capsules.

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3. Process aids

• Preservatives and surfactants are added to the gelatin solution during capsule manufacture to aid in processing.

• Gelatin solutions are an ideal medium for bacterial growth at temperatures below 55○c.

• Preservatives are added to the gelatin and colorant solutions to reduce the growth of micro-organisms until the moisture content of the gelatin film is below 16% w/v. at moisture content below that value, the bacterial population will decline in numbers with time.

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• The materials used as preservatives include :

Sulphur dioxide which is added as the sodium salts bisulfite or metabisulfite, sorbic acid or the methyl propyl esters of para hydroxy-benzoic acid, and the organic acids, benzoic and propanoic acids.

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4. 4. Plasticizers

These are used to make the softgel shell elastic and pliable. They usually account for 20-30%.

The most common plasticizers used in softgels is glycerol, although sorbitol and propylene glycol are used frequently often in combination with glycerol.

The amount and choice of the plasticizer contribute to the hardness of the final product and may even affect its dissolution or disintegration characteristics, as well as its physical and chemical stability.

The choice of plasticizer & concentration is important in ensuring optimum compatibility of shell with liquid fill matrix. 28

5. 5. Water

Water is the essential component of the soft gel shell & usually accounts for 30-40 % of the wet gel formulation and its presence is important to ensure proper processing during gel preparation and softgel encapsulation.

Following encapsulation, excess water is removed from the softgels through controlled drying. In dry gels the equilibrium water content is typically in the range 5-8% w/w, which represents the proportion of water that is bound to the gelatin in the soft gel shell.

This level of water is important for good physical stability, because in harsh storage conditions softgels will become either too soft and fuse together, or too hard and embrittled.

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6. 6. Opacifiers

An opacifiers are typically used in the wet gel formulation.

An opacifier, usually titanium dioxide may be added to produce an opaque shell when the fill formulation is a suspension, or to prevent photo degradation of light-sensitive fill ingredients.

Titanium dioxide can either be used alone to produce a white opaque shell or in combination with pigments to produce a colored opaque shell. 30

Properties of empty capsule Empty capsules contain a significant amount of

water that acts as a plasticizer for the gelatin film and is essential for their function.

The standard moisture content specification for hard gelatin capsules is between 13 % w/w and 16 % w/w. The moisture content can be maintained within the correct specification by storing them in sealed containers at an even temperature.

Capsules are readily soluble in water at 37○ C. When the temperature falls below this, their rate of solubility decreases.

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Types of materials for filling into hard gelatin capsules

Dry solids – powders, pellets, granules or tablets Semi-solids – suspensions or pastes Liquids – non-aqueous liquids

Types of excipients used in powder-filled capsules :

A. Diluents – usually present in the greatest concentration to make up necessary bulk when quantity of active ingredient is insufficient to make up the required bulk eg. Lactose, maize starch, ca. sulfate etc.

B. Lubricants and Glidants – reduce powder to metal adhesion and promote flow properties eg. Magnesium stearate, talc.

C. Wetting agents – improve water penetration for poorly soluble drugs eg. Sodium lauryl sulfate

D. Disintegrants – produce disruption of the powder mass crospovidone, sodium starch glycolate.

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Quality control of capsules

• The hard and soft gelatin capsules should be subjected to following tests for stability.

Size and shape Color Thickness of capsule shell Leaking test for semi-solid and liquid

ingredients from soft capsules Disintegration tests Dissolution test Weight variation test Percentage of medicament test

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SIZE

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1. Disintegration test

The disintegration of capsules is different from those of tablets because the determination of end point is difficult owing to the adhesive nature of shell.

The shell pieces after disintegration may agglomerate forming large mass of gelatin taking more time to dissolve and may adhere to the mesh thus, blocking the holes. 

According to USP, place one dosage unit in each of the tubes of the basket with water or any other specified medium (depends on individual monograph) maintained at 37 + 2 0 c.

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Attach a removable wire cloth with a plain square weave of 1.8-2.2 mm of mesh aperture and a wire diameter of 0.60-0.655 mm to the surface of upper rack of the basket assembly.

Observe the capsules for a time limit (specified in individual monograph), at the end of prescribed time, all of the capsules must have been disintegrated excluding the fragments from the capsule shell.

If 1 or 2 capsules fail, the test should be repeated on additional of 12 capsules.

Then, not fewer than 16 of the total 18 capsules tested should disintegrate completely.

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Dissolution

Place each of the capsules in the apparatus 1, excluding air bubbles from the surface of the capsule. Operate immediately at specified rate within specified dissolution medium at 37 + 0.5C. Aliquots should be withdrawn at specified time points mentioned in individual monograph.

The requirements are met if the quantity of active ingredients dissolved conforms the following:At stage 1 (S1): When 6 capsules are tested, amount of each of the dissolved content should not be less than +/- 5% of the mentioned in monograph.At stage 2 (S2): when 6 capsules are tested, the average of 12 (both from step 1and 2) should be equal to or greater than 15% and no capsule should be greater than 15%.

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At stage 3 (S3): when 12 capsules are tested, the average of 24 capsules (all 1,2 and 3 steps) should be equal to or greater than the amount mentioned in the monograph, not more than two units are less than 15% and no unit s less than 25%.

NOTE: 15%, 25% represent Q1 and Q2 unless and otherwise mentioned in the monograph.

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2. Weight variation test

• 20 capsules are taken at random and weighed. Their average weight is calculated, then each capsule is weighed individually and their weight noted.

• The capsule passes the test if the weight of individual capsule falls with in 90-110% of the average weight.

• If this requirement is not met, then the weight of the contents for each individual capsule is determined and compared with the average weight of the contents.

• The contents from the shells can be removed just by emptying or with the help of small brush.

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• From soft gelatin capsules the contents are removed by squeezing the shells which has been carefully cut. The remainder contents are removed by washing with a suitable solvent.

• After drying the shells, they are weighed and the content weights of the individual capsules are calculated.

• The requirements are met if :(1)not more than 2 of the differences are greater

than 10 % of the average net content and(2)in no case the difference is greater than 25 %. 40

3. Content uniformity test

Hard capsules containing 25 mg or more of the drug contents should meet content uniformity requirements.

Assay 10 capsules individually and calculate the acceptance value.

The requirement is met if the acceptance value of 10 capsules is less than or equal to 15%. If acceptance value is greater than 15% or is about 25 % then, test the next 20 units and calculate the acceptance value.

The 30 capsules if less than or equal to 15% (i.e 185-115) and no individual unit is outside 25%, (i.e 175- 125) capsule passes the test.

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Raw material

• Raw materials

• The gelatin of the capsule shells should be assayed for various physical properties like bloom strength, viscosity and its loss (by atomic force microscopy).4 Chemical tests like purity, microbial properties, and limits for heavy metals like arsenic, ash content should be determined.

• The colorants should also be checked for purity, limits for heavy metals, color properties, dye content, subsidiary dye content and color value.

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Gel Strength. • The gel strength of gelatin is a measure of the

cohesive strength of the cross-linking that occurs between gelatin molecule.

• Bloom is determined by measuring the weight in grams required to move a plastic plunger that is 0.5 inches in diameter 4mm into 6.66%gelatin gel that has been held at 100C for 17hrs.

• Bloom may vary with the requirements, ranges from 150 to 250g.

• The higher the Bloom strength of gelatin used, the more physically stable is the resulting capsule shell.

Viscosity of gelatin • Viscosity of gelatin determined on 6.66% con. of

gelatin in water at 600C. • The viscosity for gelatin can range from 25 to 45

millipoise.

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Capsule stability

• Unprotected soft capsules (i.e., capsules that can breathe) rapidly reach equilibrium with the atmospheric conditions under which they are stored.

• The variety of materials capsulated, which may have an effect on the gelatin shell, together with the many gelatin formulations that can be used, makes it imperative that physical standards are established for each product.

• The physical stability of soft gelatin capsules is associated primarily with the pick-up or loss of water by the capsule shell. 44

• If these are prevented by proper packaging, the above control capsule should have satisfactory physical stability at temperature ranging from just above freezing to as high as 60○ C, for the unprotected control capsule, low humidities (less than 20 % RH), low temperature (less than 2○ C) and high temperatures (greater than 38○

C) or combinations of these conditions have only transient effects.

The effect of temperature and humidity on capsule shell has been shown in Table below :

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• The capsule manufacturers routinely conduct accelerated physical stability tests on all new capsule products as an integral part of the product development program.

• The following tests have proved adequate for determining the effect of the capsule shell content on the gelatin shell.

• The tests are strictly relevant to the integrity of the gelatin shell and should not be confused as stability tests for the active ingredients in the capsule content.

• The results of such tests are used as a guide for the reformulation of the capsule content or the capsule shell.

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• The test conditions for such accelerated physical stability tests are shown in Table below :

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Powders and granules

Characterization of granules. Particle size & Shape determination. Surface area. Density & Packing. Granule strength & Friability. Flow properties. Moisture content. Percentage fines(% fines).

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PARTICLE SIZE & SHAPE DETERMINATION

Size affects the average weight of tablet, DT,

wt. variation ,friability, flowability & drying rate.

The size & shape depends upon processing requirements & during granulation.

The methods for determining size & shape are

1.Sieving

2.Sedimentation rate.

3.Microscopy(SEM)

4.By light scattering

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Surface area

It is not commonly used for granules but generally

used for drug substances.

If required particle size is measured & from this

surface area is measured.

Most method used is gas absorption & air

permeability.

In gas absorption, gas is absorbed as monolayer on

particles this is in term of calculated & converted to

surface area.

In air permeability method the rate of air permeates

a bed of powder is used to calculate surface area of

powder sample.

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Density

Density may influence compressability,tablet

porosity & dissolution.

Dense hard granules may require higher load to

produce cohesive compact to reduce free granules

seen on the surface of tablets.

↑ compressibility ↑ DT, Dissolution, if DT is slower

dissolution is indirectly hampered.

Dense granules have less friability but cause a

problem in releasing the drug. 51

Methods to determine density:-

1.Pycnometer:- Liquids used-Mercury -Any solvent of low surface tension e.g.

Benzene Liquids should not masks granules solubilies in it, &

having property to penetrate the pores. Density is then determine from volume of intrusion

fluid displaced in pycnometer by giving mass of granulation

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Density (D) = M/ Vp-Vi Vp - Total volume of pycnometer Vi - vol. of intrusion fluid containing mass(M) req. to fill pycnometer.2. Bulk Density:- Bulk density is given by equation ρb = M/ Vb More compressible bed of particulate less

flowable powder or Granules If less dense compressible more

flowable granules53

Granule strength and friability

They are important because they affect:-

1.changes in particle size distributions of

granulations

2.compressibility into cohesive tablets.

Granule strength & friability are measured by:-

1.Compressive Strength

2.Using Friability measurements

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Flow property

It is an ability of the granule to flow from hopper to die cavity for tablet uniformity.

Flow property of granule are not uniform we are not getting tablet of uniform size.

Flow property of material results from many forces 1.Frictional force 2.Surface tension force 3.Mechanical force caused by interlocking of irregular

shape particles 4.Electrostatic forces 5.Cohesive/ vander Waals forces

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Forces also affect granule property such as particle

size, particle size distribution, particle shape, surface

texture, roughness & surface area.

If particle size of powder is ≤ 150µm the magnitude

of frictional & vander waals force predominate.

When particle size↑ mechanical & physical

properties become more important with packing

properties.

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Fig(1)Fixed height

Fig(2)fixed base cone

Fig (3)Tilting angle

Fig (4)Rotating cylinder

In fig.(1) height is constant & powder is added through the hopper until powder reaches tip of funnel.

In fig.(2) height is varied & base cone is fixed, powder is added until height reaches at max.

In fig.(3) rectangle box is filled with powder & tipped until content begins to slide.

In fig.(4) revolving cylinder with transparent end is made to revolve horizontally when half filled with powder.

The max. angle that the plane of powder makes with horizontal surface on rotation is taken as the angle of repose.

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• (1),(2) & (3) gives static angle of repose. While (4) gives kinetic or dynamic angle of repose.

Angle of repose• The angle of repose is the angle formed by the

horizontal base of the bench surface and the edge of a cone-like pile of granules. Funnel used was a stainless steel funnel and the size of the orifice was 10 mm and the height from the beginning of funnel to end of orifice was 111 mm. The funnel was fixed in place, 4 cm above the bench surface. After the cone from 5 g of sample was built, height of the granules forming the cone (h) and the radius (r) of the base were measured. The angle of repose (θ) was calculated as follows: 59

• Results were only considered valid when a symmetrical cone of powder was formed.

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Ɵ value Flow property

Less than 30 Excellent flow

31 – 35 Good

36 - 40 Fair

41 – 45 Passable which may hang up

46 - 55 Poor which must be agitated or vibrated

greater than 56 Very poor

Moisture content

The amount of moisture present in the granule is

called moisture content.

Generally the granules contain 2% moisture. It is

required for the binding of the powder or granules

during compression in die cavity.

Percentage of moisture is calculated by using

“moisture Balance” or “IR Balance”.

IR Balance consist of simple balance which is placed

I to the casing in which the IR bulb is attached which

produce heat inside the chamber

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The small amount of sample taken from oven to

measure moisture content & place in the moisture

balance.

Initial reading should be note down after that we are

initiated the IR Bulb as IR bulb is initiated the

moisture is removed from the granules via heating

after that note down the reading.

% of moisture is calculated by,

% moisture content = Initial wt.- Final wt. 62

Percentage fineness

% fines means amount of powder remain in the

granule.

Generally the amount is 15% of fines.

It is necessary for the tablet compression because if

we are using 100% granules then it is difficult to

maintain hardness of tablet because they having

free space in the die cavity after compression the

tablet is crack due to air.

% fine can be calculated by using sieve method.

%fine should not be more than 15%.

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REFERENCES

1) Drug Stability, Principles and Practices, 3rd edition, volume-107, edited by Jens T. Carstensen, C. T. Rhodes

2) http://nsdl.niscair.res.in/bitstream/123456789/747/1/Revised+CAPSULES.pdf

3) http://uqu.edu.sa/files2/tiny_mce/plugins/filemanager/files/4290121/CAPSULES.pdf

4) The theory and practice of industrial pharmacy, 3rd edition, edited by Leon Lachman.

5) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2976911/#!po=9.37500

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