Disintegration TestDisintegration test is widely used in the pharmaceutical industry for evalution of disintigration capability offormulations (ex:tablets) and quality control of different dosage forms.

PurposeDisintegration tests are performed as per the pharmacopoeial standards. Disintegration is a measure of the quality of the oral dosage form like tablets and capsules. Each of the pharmacopoeia like the USP, BP, IP etc each have their own set of standards and specify disintegration tests of their own. USP, European pharmacopoeia and Japanese pharmacopoeia have been harmonised by the International conference on Harmonisation (ICH) and are interchangeable.

The disintegration test is performed to find out the time it takes for a solid oral dosage form like a tablet or capsule to completely disintegrate. The time of disintegration is a measure of the quality. This is because, for example, if the disintegration time is too high; it means that the tablet is too highly compressed or the capsule shell gelatin is not of pharmacopoeial quality or it may imply several other reasons. And also if the disintegration time is not uniform in a set of samples being analysed, it indicates batch inconsistency and lack of batch uniformity.

HistoryThe Swiss Pharmacopoeia, way back in 1935, required that a disintegration test should be performed on all tablets and capsules as a criterion of its performance (1). Disintegration test was seen as a test for the uniformity of the compressional characteristics. Optimisation of compression characteristics was done based on disintegration test and the hardness test. Modern medicine era may be considered

to be starting from 1937, and from this year tablets became important (2). Tabletting technology was mostly empirical upto the year 1950. Till this year, i.e., 1950, formulators depended on disintegration test, largely, to optimise their compression characteristics. Drug release testing by way ofdissolution testing was not much used to characterise the tablets, probably because, by that time, convenient and sensitive chemical analyses were not available before this period.The British Pharmacopoeia was the first, in 1945, to adopt an official disintegration test. Before 1950, the test became official in USP also. Even at that time, it was recognised that disintegration does not ensure good performance. USP-NF of that period says “ disintegration does not imply complete solution of the tablet or even of its active ingredient.” In the year 1950, sporadic reports of tablet products of vitamins failing to release their total drug content started appearing. It was only then that formulators realised that though the tablets/capsules showed required disintegration time, they might show poor dissolution, which might effect its clinical performance. Chapman et al., demonstrated that formulations with long disintegration times might not show good bioavailability. Later, John Wagner demonstrated the relationship between poor performance of some drug products in disintegration tests and their failure to release the drug during their gastrointestinal transit. In the 1960s two separate developments occurred. One is the development of sensitive instrumental methods of analysis and the other is the growth of a new generation of pharmaceutical scientists who started applying the principles of physical chemistry to pharmacy. This development was attributed in USA to Takeru Higuchi and his students. In the

later period more pharmaceutical scientists like, Campagna, Nelson, and Levy worked on this field and more and more instances of lack of correlation between disintegration time and bioavailability surfaced. It was in the year 1970 that the first dissolution apparatus, the rotating basket was designed and adopted in the USA. An excellent review on disintegration test was written by Wagner in 1971 (3).Disintegration Test Apparatus

Coming to the test, the disintegration test is conducted using the disintegration apparatus. Although there are slight variations in the different pharmacopoeias, the basic construction and the working of the apparatus remains the same. The apparatus consists of a basket made of transparent polyvinyl or other plastic material. It has 6 tubes set into the same basket with equal diameter and a wire mesh made of stainless steel with uniform mesh size is fixed to each of these six tubes. Small metal discs may be used to enable immersion of the dosage form completely. The entire basket-rack assembly is movable by reciprocating motor which is fixed to the apex of the basket-rack assembly. The entire assembly is immersed in a vessel containing the medium in which the disintegration test is to be carried out. The vessel is provided with a thermostat to regulate the temperature of the fluid medium to the desired temperature.

Disintegration Test Method

The disintegration test for each dosage form is given in the pharmacopoeia. There are some general tests for typical types of dosage forms. However, the disintegration test prescribed in the individual monograph of a product is to be followed. If the monograph does not specify any specific test, the general test for the specific dosage form may be employed. Some of the types of dosage forms and their

disintegration tests are:1.Uncoated tablets- Tested using distilled water as medium at 37+/-2 C at 29-32 cycles per minute; test is completed after 15 minutes. It is acceptable when there is no palpable core at the end of the cycle (for at least 5 tablets or capsules) and if the mass does not stick to the immersion disc.2.Coated tablets- the same test procedure is adapted but the time of operation is 30 minutes.3.Enteric coated/ Gastric resistant tablets- the test is carried out first in distilled water (at room temperature for 5 min.; USP and no distilled water per BP and IP), then it is tested in 0.1 M HCL (upto 2 hours; BP) or Stimulated gastric fluid (1 hour; USP) followed by Phosphate buffer, pH 6.8 (1 hour; BP) or Stimulated intestinal fluid without enzymes (1 hour; USP).4.Chewable tablets- exempted from disintegration test (BP and IP), 4 hours (USP).These are a few examples for illustration. The disintegration tests for capsules, both hard and soft gelatin capsules are also performed in a similar manner. Also, the USP also provides disintegration tests for suppositories, pessaries etc.

Applications of Disintegration test :

1.Disintegration test is a simple test which helps in the preformulation stage to the formulator.2.It helps in the optimisation of manufacturing variables, such as compressional force and dwell time.3.This test is also a simple in-process control tool to ensure uniformity from batch to batch and among different tablets4.It is also an important test in the quality control of tablets and hard gelatine capsules.

Advantages of Disintegration tests:

This test is simple in concept and in practice.It is very useful in preformulation, optimisation and in quality control.

Disadvantages:

Disintegration test cannot be relied upon for the assurance of bioavailability.

Books for further studying Disintegration test

1.The Theory and practice of Industrial Pharmacy by Leon Lachman and Herbert A. Lieberman, CBS Publishers and distributors, New Delhi.2.Pharmaceutical Dissolution Testing, edited by Jennifer Dressman and Johannes Kramer, Taylor & Francis publications3.Pharmaceutical Dosage Forms and Drug Delivery Systems by Howard C. Ansel, Loyd V. Allen, Jr.,and Nicholas G.Popovich; Seventh Edition, Lippincott Williams & Wilkins publishers.

Review articles on Disintegration test:1.http://pharmtech.findpharma.com/pharmtech/Formulation+Article/An-Alterna... [Accessed on 24th July 2010]2. http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T7W-4PJM9JC-2... [Accessed on 24th July 2010]3.http://www.dissolutiontech.com/DTresour/201002Articles/DT201002_A01.pdf4. http://www.ncbi.nlm.nih.gov/pubmed/17935916[Accessed on 24th July 2010]References1.History of dissolution testing,2000. dissolution Solutions Network, website,

http://www.dissolutionsolutions.net/?page_id=38 (accessed Janary14th, 2010 [Accessed on 24th July 2010]2.Pharmaceutical Dissolution Testing, by Jennifer Dressman and Johannes Kramer, Taylor & Francis Publications, pages 5,6. [Accessed on 24th July 2010]3.Wagner J.G.: Biopharmaceutics and relevant Pharmacokinetics, Drug Intelligence Publications, Hamilton, IL, 1971, p.64. [Accessed on 24th July 2010]4. The Indian pharmacopoeia,1996 [Accessed on 24th July 2010]5. British pharmacopoeia,2009 [Accessed on 24th July 2010]6. United States NF, 2008 (http://www.usp.org/pdf/EN/USPNF/chapter701.pdf ). [Accessed on 24th July 2010]

Dissolution

1.5. DissolutionDissolution is the process by which a solid solute enters a solution. In the pharmaceutical industry, it may be defined as the amount of drug substance that goes into solution per unit time under standardized conditions of liquid/solid interface, temperature and solvent composition. Dissolution is considered one of the most important quality control tests performed on pharmaceutical dosage forms and is now developing into a tool for predicting bioavailability, and in some cases, replacing clinical studies to determine bioequivalence. Dissolution behaviour of drugs has a significant effect on their pharmacological activity. In fact, a direct relationship between in vitro dissolution rate of many drugs and their bioavailability has been demonstrated and is generally referred to as i n vitro-in vivo correlation, IVIVC 38 .

Solid dosage forms may or may not disintegrate when they interact with gastrointestinal fluid following oral administration depending on their design (Figure 1). For disintegrating solid oral dosage forms, disintegration usually plays a vital role in the dissolution process since it determines to a large extent the area of contact between the solid and liquid. However it is well known that considerable dissolution of the drug can take place before complete disintegration of the dosage form, a phenomenon which depends largely on the mechanism of disintegration and certain physicochemical properties of the drug, such as its solubility. This could be important when considering the motility of the drug or dosage form, and the release of the

drug at specific sites, in the gastrointestinal tract. Thus, correlations have been established between disintegration times and dissolution rates for various pharmaceutical tablets 7, 39-42 . It should be noted, however, that there is not always an automatic correlation between disintegration and dissolution, especially for drugs with very low dissolution rates.

For many drugs, particularly those that are poorly soluble in the gastric fluid, the rate-limiting step in the absorption process is the dissolution rate and a dissolution rate determination can therefore be a useful guide to comparative bioavailability 43 . Since drug absorption and physiological availability depend on the availability of the drug substance in the dissolved state, suitable dissolution characteristics are important property for a satisfactory tablet. The dissolution test measures the amount of time required for certain percentage of the drug substance in a tablet to go into solution under a specified set of conditions. It describes a step towards physiological availability of the drug substance, but it is not designed to measure the safety or efficacy of the tablet being tested 44 . It provides in vitro control procedure to eliminate variation among production batches. The dissolution medium must be aqueous and the pH of the medium should be controlled and should simulate in vivoconditions. The dissolution medium should be 0.1M HCl and pH 6.8 buffer to simulate the biological extremes. The possible role of bile salts in absorption of highly insoluble drugs suggests the inclusion of physiological concentrations of sodium taurocholate in the mildly acid or alkaline media. Studies have shown that low agitation must be used (i.e. in the order of 50rpm) and that

the tablet must not be subjected to abrasion in keeping with the mild agitation in the gastrointestinal tract 45 .

Figure 1: Schematic diagram of the dissolution process

Dissolution kinetics is important in determining the bioavailability of a drug 39 . Levy 45 and some other workers46 reported that the dissolution rate controls the rate of build up of certain drugs in the blood stream. It was thus recognized that in-vitro dissolution kinetics provides useful information on the availability of drugs and their subsequent therapeutic effects in-vivo 45 . This led to the inclusion of dissolution tests in the United States NF XIII (1970) andUSP XVIII (1970) monographs for one capsule and twelve tablet preparations. In 1975, dissolution tests were included in the British Pharmacopoeia (amendment to BP 1973) for digoxin tablets. The various pharmacopoeias contain specifications on the dissolution requirements of various drugs. A variety of designs of apparatus for dissolution testing have been proposed and tested, varying from simple beaker with stirrer to complex systems with lipid phases and lipid barrier where an attempt is made to mimic the biological milieu. The choice of the apparatus to be used

depends largely on the physicochemical properties of the dosage form47 .

Dissolution Test

Dissolution testing is widely used in the pharmaceutical industry for optimization of 

formulation and quality control of different dosage forms.Definition   Purpose   History   ApplicationsArticlesReferencesWhat is the definition of dissolution ?Dissolution is pharmaceutically defined as the rate of mass transfer from a solid surface into the dissolution medium or solvent under standardized conditions of liquid/solid interface, temperature and solvent composition. It is a dynamic property that changes with time and explains the process by which a homogenous mixture of a solid or a liquid can be obtained in a solvent. It happens to chemically occur by the crystal break down into individual ions, atoms or molecules and their transport into the solvent.Why dissolution testing is used for pharmaceuticals ?

Dissolution testing is a critical preformulation solubility analysis research tool in the process of drug discovery that

entails measuring the stability of the investigational product, achieving uniformity in production lots and determining its in vivo availability. Thus this Dissolution testing is an essential requirement for the development, establishment of in vitro dissolution and in vivo performance (IVIVR), registration and quality control of different dosage forms.

What is the history of the dissolution testing ?Dissolution testing has almost had a century of development. It expanded over years beyond the ordinary Tablets and Capsules, first to Extended-release and Delayed-release (enteric-coated) articles, then to transdermals, Multivitamin and Minerals products, and to Class Monographs for non-prescription drug combinations. It was in the year 1897 that Noyes and Whitney published a paper on “Rate of solution of solid substances in their own solution” which gave the first known reference to dissolution testing. In this paper, they suggested that a layer of saturated solution that forms instantly around a solid particle controls the dissolution rate. Later in 1900, Brunner and Tolloczko proved and listed the factors determining the dissolution rate as chemical and physical structures of the solid, the surface area exposed to the medium, agitation speed, medium temperature and the overall design of the dissolution apparatus. In 1904, Nernst and Brunner established a relationship between the dissolution rate and the diffusion coefficient by developing a modified Noyes-Whitney equation with the application of Fick’s law of diffusion to it. In 1930, Experiments on dissolution testing began with in vivo-In vitro correlations and in 1931, Hixon and Crowell developed the cube-root law of diffusion. In 1934, disintegration test   was introduced for tablets by the Swiss Pharmacopoeia Helvetica but it became an official

United States Pharmacopoeia (USP) method only in 1950. During this period, the emphasis also moved from studying the effects of physicochemical properties of drug on dissolution to correlation of dissolution to bioavailability of dosage forms. In 1958, a rotating bottle dissolution method was developed for extended release formulations. The USPrecognized a need for a standardized dissolution test and began experimenting with a variety of basket and stirring devices during the 1960s. Levy and Hayes4 utilized a beaker blade stirrer at 30-60rpm and found significant differences in the in vitro dissolution rates of different brands of aspirin tablets which linked to the incidence of gastric irritation caused by various brands due to their slow dissolution rates. The first official dissolution test for solid dosage forms using a rotating basket was incorporated by USP 18 in 1970. In 1975, the USP began developing of calibrators for dissolution testing and in 1978, it proposed three calibrator tablets – prednisone (disintegrating), salicylic acid (non-disintegrating) and nitrofurantoin (disintegrating), but no predefined calibration frequency was made. In the same year 1978, the Food Drug Administration (FDA) published guidelines for Dissolution Testing. In 1990, the paddle over disk, rotating cylinder and the Reciprocating Disk dissolution apparatus models were developed and later in 1995, the reciprocating cylinder and the flow-through cell were developed.What are the applications of dissolution tesing ?

Dissolution testing is widely used in the pharmaceutical industry for optimization of formulation and quality control.It is useful in the pharmaceutical and biotechnology industry to formulate drug dosage forms and to develop quality

control specifications for its manufacturing process.To identify the critical manufacturing variable, like the binding agent effect, mixing effects, granulation procedure, coating parameters and comparative profile studies.

To comply with guidelines set in the scale up and post

approval changes (SUPAC) and ICH.

To select candidate formulation

To simulate food effect on bio availability.

To support waiver for bio equivalence requirements.

In the study of Bio waivers.

As a Surrogate for invivo studies.

In the In vitro invivo correlations.

Theories of dissolution

1.5.1 . Theories of dissolutionSome workers 48,49 have reviewed the factors which can affect the dissolution of tablets and these include the stirring speed, temperature, viscosity, pH, composition of the dissolution medium and the presence or absence of wetting agents.

Physical models have been set up to account for the observed dissolution of tablets. According to Higuchi 50, there are three models which either alone or in combination, can be used to describe the dissolution mechanisms. These are:

(i) The Diffusion layer model

This model (Fig 2) assumes that a layer of liquid, H cm thick, adjacent to the solid surface remains stagnant as the bulk liquid passes over the surface with a certain velocity. The reaction at the solid/liquid interface is assumed to be instantaneous forming a saturated solution, C s , of the solid in the static liquid film. The rate of dissolution is governed entirely by the diffusion of the solid molecules from the static liquid film to the bulk liquid according to Fick’s first law:

J = - D f dc / dx (4)

where J is the amount of substance passing perpendicularly through a unit surface area per time, D f ,is the diffusion coefficient and dc / dx, is the concentration gradient. After a time t, the concentration between the limit of the static liquid layer and the bulk liquid becomes C t . Once the solid

molecules pass into the bulk liquid, it is assumed that there is rapid mixing and the concentration gradient disappears.

The theory predicts that if the concentration gradient is always constant i. e. C s - C t is constant because C s >> C t(“sink” conditions which usually mean C s > 10 C t ) then a uniform rate of dissolution is obtained.

Fig. 2 . Diffusion Layer Model

(ii) The Interfacial Barrier Model

In the interfacial barrier model (Fig 3), it is assumed that the reaction at the solid/liquid interface is not instantaneous due to a high activation free energy barrier which has to be surmounted before the solid can dissolve. Thereafter the dissolution mechanism is essentially the same as in (i) above, with the concentration at the limit of the static layer of liquid becoming C t after time t.

The rate of diffusion in the static layer is relatively fast in comparison with the surmounting of the energy barrier, which therefore becomes rate limiting in the dissolution process.

Fig. 3 . Diagrammatic representation of the free energy barrier to dissolution

(iii) The Danckwert’s Model

The Danckwert’s model (Fig 4) assumes that macroscopic packets of solvent reach the solid/liquid interface by eddy diffusion in some random fashion.

Fig. 4 . The Danckwert’s Model.

At the interface, the packet is able to absorb solute according to the laws of diffusion and is then replaced by a new packet of solvent. This surface renewal process is related to the solute transport rate and hence to the dissolution rate.

The rate laws predicted by the different mechanisms both alone and in combination, have been discussed by Higuchi 50 . However, the earliest equation expressing

dissolution rate in a quantitative manner was proposed by Noyes and Whitney51 as:-

dc / dt = k (C s - C t ) (5)

where dc / dt is the rate of change in concentration with respect to time, and k is the rate constant. The integrated form of the equation is:

In [C s / (C s - C t ) ] = kt (6)

The equation in resemblance to the other rate law equations50 , predicts a first order dependence on the concentration gradient (i.e. C s - C t ) between the static liquid layer next to the solid surface and the bulk liquid. Noyes and Whitney explained their dissolution data using a concept similar to that used for the diffusion model 50 . This considerations relate to conditions in which there is no change in the shape of the solid during the dissolution process ( i. e. the surface area remains constant). However, for pharmaceutical tablets, disintegration occurs during the dissolution process and the surface area generated therefore varies with time.

Aguiar et al 52 proposed a scheme which holds that dissolution occurs only when the drug is in small particles. Wagner 53 modified this idea and showed that dissolution occurs from both the intact tablet and the aggregates and/or granules produced after disintegration by using a plot of the percentage of drug dissolved versus time on logarithmic - probability graph papers.

A modification of this approach was proposed by Kitazawa et al 54,55 . Employing the integrated form of Noyes and Whitney equation (equation 6), they determined the dissolution rate constant of uncoated caffeine tablets. The Kitazawa

equations have been used to determine the dissolution rates of some pharmaceutical tablet formulations7,25,41,42 .