Disintegration Test Disintegration test is widely used in the pharmaceutical industry for evalution of disintigration capability offormulations (ex:tablets

) and quality control of different dosage forms.

Purpose
Disintegration 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.

History
The 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

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

later period more pharmaceutical scientists like. Campagna. the basic construction and the working of the apparatus remains the same. Small metal discs may be used to enable immersion of the dosage form completely. Disintegration Test Method The disintegration test for each dosage form is given in the pharmacopoeia. Although there are slight variations in the different pharmacopoeias. Disintegration Test Apparatus Coming to the test. Some of the types of dosage forms and their . An excellent review on disintegration test was written by Wagner in 1971 (3). the disintegration test prescribed in the individual monograph of a product is to be followed. the rotating basket was designed and adopted in the USA. 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. However. and Levy worked on this field and more and more instances of lack of correlation between disintegration time and bioavailability surfaced. The apparatus consists of a basket made of transparent polyvinyl or other plastic material. If the monograph does not specify any specific test. the general test for the specific dosage form may be employed. Nelson. It was in the year 1970 that the first dissolution apparatus. the disintegration test is conducted using the disintegration apparatus. The vessel is provided with a thermostat to regulate the temperature of the fluid medium to the desired temperature. 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. There are some general tests for typical types of dosage forms.

such as compressional force and dwell time. 2.Chewable tablets. both hard and soft gelatin capsules are also performed in a similar manner. USP) followed by Phosphate buffer. These are a few examples for illustration.Uncoated tablets. 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.Disintegration test is a simple test which helps in the preformulation stage to the formulator. Also.1 M HCL (upto 2 hours.the test is carried out first in distilled water (at room temperature for 5 min.Enteric coated/ Gastric resistant tablets. BP) or Stimulated gastric fluid (1 hour. test is completed after 15 minutes. USP). 3. 4. pessaries etc.the same test procedure is adapted but the time of operation is 30 minutes.Tested using distilled water as medium at 37+/-2 C at 29-32 cycles per minute. BP) or Stimulated intestinal fluid without enzymes (1 hour.exempted from disintegration test (BP and IP). The disintegration tests for capsules. the USP also provides disintegration tests for suppositories. Advantages of Disintegration tests: .8 (1 hour. 4 hours (USP). 3. USP and no distilled water per BP and IP).It is also an important test in the quality control of tablets and hard gelatine capsules. then it is tested in 0.It helps in the optimisation of manufacturing variables. Applications of Disintegration test : 1. 2..This test is also a simple in-process control tool to ensure uniformity from batch to batch and among different tablets 4. pH 6.disintegration tests are: 1.Coated tablets.

. dissolution Solutions Network.nlm. Lippincott Williams & Wilkins publishers.and Nicholas G.ncbi.net/?page_id=38 (accessed . website. It is very useful in preformulation.com/pharmtech/Formulation +Article/An-Alterna. Disadvantages: Disintegration test cannot be relied upon for the assurance of bioavailability. Taylor & Francis publications 3. Books for further studying Disintegration test 1.dissolutiontech. [Accessed on 24th July 2010] 2. edited by Jennifer Dressman and Johannes Kramer.The Theory and practice of Industrial Pharmacy by Leon Lachman and Herbert A.nih. optimisation and in quality control.com/DTresour/201002Articles/ DT201002_A01.http://www. http://www.. 2. Loyd V. Allen. Jr.pdf 4. Ansel..Pharmaceutical Dosage Forms and Drug Delivery Systems by Howard C. [Accessed on 24th July 2010] 3.com/science? _ob=ArticleURL&_udi=B6T7W-4PJM9JC-2.2000.sciencedirect.History of dissolution testing..findpharma. Review articles on Disintegration test: 1.dissolutionsolutions. Seventh Edition. http://www.. Lieberman.Pharmaceutical Dissolution Testing. CBS Publishers and distributors.http://pharmtech.This test is simple in concept and in practice. New Delhi.gov/pubmed/17935916[Accesse d on 24th July 2010] References 1. http://www.Popovich.

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

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. IVIVC 38 . and in some cases. it may be defined as the amount of drug substance that goes into solution per unit time under standardized conditions of liquid/solid interface. . in the gastrointestinal tract. In fact. This could be important when considering the motility of the drug or dosage form. a phenomenon which depends largely on the mechanism of disintegration and certain physicochemical properties of the drug.5.Dissolution 1. In the pharmaceutical industry. Solid dosage forms may or may not disintegrate when they interact with gastrointestinal fluid following oral administration depending on their design (Figure 1). and the release of the drug at specific sites. For disintegrating solid oral dosage forms. However it is well known that considerable dissolution of the drug can take place before complete disintegration of the dosage form. such as its solubility. Dissolution Dissolution is the process by which a solid solute enters a solution. replacing clinical studies to determine bioequivalence. temperature and solvent composition. Thus. 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. Dissolution behaviour of drugs has a significant effect on their pharmacological activity. 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.

especially for drugs with very low dissolution rates.e.8 buffer to simulate the biological extremes.correlations have been established between disintegration times and dissolution rates for various pharmaceutical tablets 7. that there is not always an automatic correlation between disintegration and dissolution. 39-42 . . 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. suitable dissolution characteristics are important property for a satisfactory tablet. 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 . Studies have shown that low agitation must be used (i. 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. It describes a step towards physiological availability of the drug substance. For many drugs. 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 . The dissolution medium must be aqueous and the pH of the medium should be controlled and should simulate in vivoconditions. but it is not designed to measure the safety or efficacy of the tablet being tested 44 . particularly those that are poorly soluble in the gastric fluid. It provides in vitro control procedure to eliminate variation among production batches. The dissolution medium should be 0. It should be noted.1M HCl and pH 6. Since drug absorption and physiological availability depend on the availability of the drug substance in the dissolved state. however.

Levy 45 and some other workers46 reported that the dissolution rate controls the rate of build up of certain drugs in the blood stream. 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. The various pharmacopoeias contain specifications on the dissolution requirements of various drugs. dissolution tests were included in the British Pharmacopoeia (amendment to BP 1973) for digoxin tablets. In 1975. A variety of designs of apparatus for dissolution testing have been proposed and tested. The choice of the apparatus to be used depends largely on the physicochemical properties of the dosage form47 . 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. .Figure 1: Schematic diagram of the dissolution process Dissolution kinetics is important in determining the bioavailability of a drug 39 . 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 .

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 Applications Articles References What 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. achieving uniformity in production lots and determining its in vivo availability. 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. atoms or molecules and their transport into the solvent. Thus this Dissolution testing is an essential . It happens to chemically occur by the crystal break down into individual ions. 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.

Later in 1900. In 1904. agitation speed. Hixon and Crowell developed the cube-root law of diffusion. In 1930. the surface area exposed to the medium. Multivitamin and Minerals products. What is the history of the dissolution testing ? Dissolution testing has almost had a century of development. they suggested that a layer of saturated solution that forms instantly around a solid particle controls the dissolution rate. the emphasis also moved from studying the effects of physicochemical properties of drug on . then to transdermals. registration and quality control of different dosage forms. medium temperature and the overall design of the dissolution apparatus. Brunner and Tolloczko proved and listed the factors determining the dissolution rate as chemical and physical structures of the solid. Experiments on dissolution testing began with in vivo-In vitro correlations and in 1931. disintegration test was introduced for tablets by the Swiss Pharmacopoeia Helvetica but it became an official United States Pharmacopoeia (USP) method only in 1950. establishment of in vitro dissolution and in vivo performance (IVIVR). In 1934. During this period. It expanded over years beyond the ordinary Tablets and Capsules.requirement for the development. and to Class Monographs for non-prescription drug combinations. Nernst and Brunner established a relationship between the dissolution rate and the diffusion coefficient by developing a modified NoyesWhitney equation with the application of Fick’s law of diffusion to it. first to Extended-release and Delayed-release (enteric-coated) articles. In this paper. 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.

the USP began developing of calibrators for dissolution testing and in 1978. In 1990. In 1958. like the . 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. The first official dissolution test for solid dosage forms using a rotating basket was incorporated by USP 18 in 1970. but no predefined calibration frequency was made. What are the applications of dissolution tesing ? Dissolution testing is widely used in the pharmaceutical industry for optimization of formulation and quality control. it proposed three calibrator tablets – prednisone (disintegrating). rotating cylinder and the Reciprocating Disk dissolution apparatus models were developed and later in 1995. salicylic acid (non-disintegrating) and nitrofurantoin (disintegrating). In the same year 1978. To identify the critical manufacturing variable. the Food Drug Administration (FDA) published guidelines for Dissolution Testing. the paddle over disk. It is useful in the pharmaceutical and biotechnology industry to formulate drug dosage forms and to develop quality control specifications for its manufacturing process.dissolution to correlation of dissolution to bioavailability of dosage forms. 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 reciprocating cylinder and the flow-through cell were developed. In 1975.

• As a Surrogate for invivo studies. granulation procedure. To comply with guidelines set in the scale up and post approval changes (SUPAC) and ICH. • To support waiver for bio equivalence requirements. • To select candidate formulation • To simulate food effect on bio availability. • . • In the study of Bio waivers.binding agent effect. mixing effects. coating parameters and comparative profile studies. • In the In vitro invivo correlations.

pH.D f dc / dx (4) where J is the amount of substance passing perpendicularly through a unit surface area per time. .5. composition of the dissolution medium and the presence or absence of wetting agents. there are three models which either alone or in combination. adjacent to the solid surface remains stagnant as the bulk liquid passes over the surface with a certain velocity. Physical models have been set up to account for the observed dissolution of tablets. According to Higuchi 50. of the solid in the static liquid film. The reaction at the solid/liquid interface is assumed to be instantaneous forming a saturated solution. H cm thick. the concentration between the limit of the static liquid layer and the bulk liquid becomes C t . After a time t.1 .is the diffusion coefficient and dc / dx. it is assumed that there is rapid mixing and the concentration gradient disappears. 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 = . viscosity. C s . Theories of dissolution Some workers 48.Theories of dissolution 1. These are: (i) The Diffusion layer model This model (Fig 2) assumes that a layer of liquid. Once the solid molecules pass into the bulk liquid. D f . is the concentration gradient.49 have reviewed the factors which can affect the dissolution of tablets and these include the stirring speed. can be used to describe the dissolution mechanisms. temperature.

Fig. with the concentration at the limit of the static layer of liquid becoming C t after time t. Diffusion Layer Model (ii) The Interfacial Barrier Model In the interfacial barrier model (Fig 3). The rate of diffusion in the static layer is relatively fast in comparison with the surmounting of the energy barrier. .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. 2 .The theory predicts that if the concentration gradient is always constant i. which therefore becomes rate limiting in the dissolution process. Thereafter the dissolution mechanism is essentially the same as in (i) above. C s . 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. e.

The Danckwert’s Model. Fig. 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. The rate laws predicted by the different mechanisms both alone and in combination.Fig. have been discussed by Higuchi 50 . At the interface. 3 . the earliest equation expressing . 4 . However. This surface renewal process is related to the solute transport rate and hence to the dissolution rate. the packet is able to absorb solute according to the laws of diffusion and is then replaced by a new packet of solvent.

e.C t ) (5) where dc / dt is the rate of change in concentration with respect to time. predicts a first order dependence on the concentration gradient (i. they determined the dissolution rate constant of uncoated caffeine tablets. Employing the integrated form of Noyes and Whitney equation (equation 6). Noyes and Whitney explained their dissolution data using a concept similar to that used for the diffusion model 50 .dissolution rate in a quantitative manner was proposed by Noyes and Whitney51 as:dc / dt = k (C s . 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. disintegration occurs during the dissolution process and the surface area generated therefore varies with time. A modification of this approach was proposed by Kitazawa et al 54. This considerations relate to conditions in which there is no change in the shape of the solid during the dissolution process ( i. e. C s . for pharmaceutical tablets.C t ) between the static liquid layer next to the solid surface and the bulk liquid.C t ) ] = kt (6) The equation in resemblance to the other rate law equations50 . However. and k is the rate constant. The integrated form of the equation is: In [C s / (C s .55 . Aguiar et al 52 proposed a scheme which holds that dissolution occurs only when the drug is in small particles. the surface area remains constant). The Kitazawa .

.equations have been used to determine the dissolution rates of some pharmaceutical tablet formulations7.25.42 .41.