What is the difference between dissolve and disintegrate

Anonymous 27 December at Unknown 29 December at Unknown 5 January at Unknown 28 March at Sajid Hassan 22 October at Unknown 28 October at Unknown 10 April at Unknown 12 August at Unknown 2 September at Unknown 19 November at It also must be noted that a gaseous solvent can be dissolved only through another gaseous solute by a person. This kind of process is a kind of a kinetic process. The kinetic energy that is exerted out of the temperature rise will help in speeding up the process of dissolution for solutes.

In the case of a solid substance, that substance can usually be dissolved only by shaking, but not all substances would dissolve just by shaking, and some may need to go through the process of breaking down. The example of tablets getting dissolved in water is all examples of effective dissolution. In chemical reactions, the compounds are made to disintegrate. Many a time, the process of dissolution can clash with the process of disintegration. This is when water solvent gets directly soluble in small pieces of a solid substance.

Bell and Peppas [ ] developed another apparatus to investigate the swelling behaviour of crosslinked hydrophilic polymers under an applied load as a function of time and absorbed weight. Apparatus to measure the disintegration force and the water uptake of a tablet. The tablet is clamped between the punch tip and the glass disk modified from [ ].

Using the swelling force and water uptake measurements, it was possible to relate different disintegrants to specific disintegration mechanisms, i. These findings were supported by a study from Desai et al. They concluded that there was no significant swelling associated with XPVP in free and compacted particles. However, the effect of compression force on the disintegration of compacts containing XPVP strongly indicated that strain recovery is the major mechanism for XPVP disintegrant action.

It was further shown on the basis of force and water uptake measurements that disintegration times of tablets with a swelling disintegrant are only slightly affected by relative tablet density, whereas the strain recovery disintegrant requires high relative densities for rapid disintegration [ ]. The water uptake rate is in particular influenced by the permeability of the powder compact as discussed in the previous section. In order to simultaneously study the penetration of liquid, microstructural changes and swelling, one needs to adequately visualise the process of disintegration from within a tablet in a non-destructive and contactless manner.

Magnetic resonance imaging MRI was used very successfully to generate cross-sectional images of modified-release tablets during the exposure to liquid [ — ] and thus it was primarily used to study slow mass transport and swelling kinetics over a time scale of hours.

However, Tritt-Gloc and Kowalczuk [ ] employed dynamic MRI to study the disintegration behaviour of paracetamol tablets in-vitro under acidic gastric pH conditions. The authors estimated disintegration profiles on the basis of the MRI images for different commercial tablets containing paracetamol and for different fluid temperatures. The improvements in terms of acquisition speed and resolution enabled a more detailed analysis compared to the setup presented by Tritt-Gloc and Kowalczuk [ ].

The quantitative evaluation of the MRI data was performed on the basis of the grey value distribution of each image yielding information about the distribution and relative amount of water within a tablet during disintegration. This analysis was applied to differentiate the disintegration action of different disintegrants, where the results indicated differences between SSG swelling , CCS swelling , polacrilin potassium PP, swelling and XPVP strain recovery disintegrants [ 44 ].

The same group also presented an alternative data processing method of the MRI data [ ], which calculates fractal dimensions of tablet boundaries Fig. The fractal dimension is directly related to the surface area of a tablet and thus provides information about the effectiveness of the disintegration. However, this method could not sufficiently differentiate between tablets of varying relative densities and it only covers the initial phase rather than the complete course of the disintegration process.

Quantitative analysis of tablet disintegration by MRI. Subsequently the edges are detected as depicted in b , which is used for the calculation of the fractal dimension. This procedure was applied on MRI measurements of tablets with different disintegrants and analysed as a function of time as depicted in c. Relative density differences and elastic properties of tablets can be studied by means of non-destructive ultrasonic measurements [ ].

Akseli et al. The authors applied machine learning concepts neural networks, genetic algorithms, support vector machines and random forest to predict the disintegration time from ultrasonic measurements and several other tablet properties tablet diameter, thickness, weight, porosity and breaking force as well as process parameters compression force and tablet compaction speed. The use of such statistical models may provide high correlation results, but one has to be careful when training such models to avoid overfitting and to assess generalisability.

Moreover, statistical models do not reflect physical properties of the powder compact and thus no fundamental insights about disintegration phenomena can be gained from such models. However, the use of the ultrasound technique provides some very interesting insights into the internal structure of tablets and can be used as a very powerful sensor for in-die measurements during compaction process development [ , ]. A promising new technique to measure tablet disintegration is terahertz pulsed imaging TPI.

Most pharmaceutical excipients are transparent to terahertz radiation far-infrared and sub-millimetre regime of the electromagnetic spectrum. In TPI short pulses of this radiation are focused on the dosage form of interest and the reflected echoes are recorded as a function of their time-of-flight, much like ultrasound or radar experiments [ ]. Given the transparency of the tablet matrix to terahertz radiation information from both surface and internal structure of the dosage form can be measured in the same experiment.

The terahertz pulse can propagate through the entire dosage form and reflections will be detected at every interface where the refractive index of the medium is changing such as internal cracks or the liquid front of penetrating liquid into the tablet [ , ]. This principle enables the monitoring of the swelling and the liquid ingress as shown in Fig.

Yassin et al. In addition, it is possible to detect cracks that can form in some matrices due to the strain exerted by the hydration. Given the measurements are fast acquisition rates of less than 10 ms have previously been reported [ ] the method is very well suited to investigate the disintegration of immediate-release tablets. Schematic of the experimental setup for the in-situ monitoring of the disintegration process by TPI and the deconvolved time-domain terahertz waveforms each line is offset by 0.

Using the TPI method the effect of porosity and water temperature on the disintegration was investigated in detail. The rates of swelling and wicking were found to correlate with the porosity of the tablet and could be described by a simple Darcy flow model Fig. The shading marks the standard deviation between individual experimental repeats. In a further study the effect of different binders, lubricants and disintegrants was studied [ ].

Lubricants are highly hydrophobic materials, which significantly affect the wettability of the porous matrix. Therefore, a lubricant is expected to retard water penetration and thus the onset of disintegration and dissolution [ , ]. The mass fraction of the lubricant is a critical factor as a minimum amount is required to cover the surface of the particles and thus to fully exploit the functionality of the lubricant [ , ].

Given that anomalous transport processes result in inconsistent hydration and disintegration kinetics, and thus increases batch variability, this regime is not an ideal hydration mechanism for tablet disintegration. The study further revealed that there is a critical concentration of binder for a tablet formulation which will change the tablet properties and dominate both the hydration and disintegration kinetics. However, more work is required to understand the relation of lubricant and binder concentration to tablet disintegration kinetics in more detail.

Several research groups determined the particle size distribution of the detached particles directly. Shotton and Leonard [ 99 , ] used a combination of a wet sieving technique and a Coulter Counter to investigate the impact of intra - and extra -granular incorporation of the disintegrant. They concluded that intra -granular incorporation leads to smaller mean particle size, whereas the disintegration time was longer. In general, a smaller particle size causes a faster dissolution see Eq.

Several other studies used video imaging to count the number of detached particles and to measure their size [ 20 , 43 , , ]. Quodbach et al. The detected particle size varied highly between the beginning and the end of the disintegration process and also between different disintegrants. They evinced that a further disintegration of particles occurs after break up of the tablet core, which was also indicated by Zhao et al. Particle size of disintegrated particles as a function of time measured by modified spatial filtering velocimetry.

The rows he colour codes are the relative percentage of a given particle size. The particle size developing over time is depicted in c and d for SSG and PP, respectively modified from [ ]. As highlighted in the previous section, the bioavailability of the dosage form can be significantly influenced by the GI environment. Several research groups investigated regional differences in the GI to gain more knowledge about the influence of theGI environment, as well as more predictable in-vitro in-vivo correlations [ ].

However, the application of ionising radiation to humans is mostly restricted by national laws on radiation protection and therefore, there was the need to find alternative methods like biomagnetic techniques. Magnetic sensors used for such investigations typically employ induction coils to measure biomagnetic fields resulting from ferromagnetic sources in response to an applied magnetic field.

Thus, the samples must be labelled by magnetic materials, which is achieved by the incorporation of powdered ferromagnetic substances e. The technique of magnetic marker monitoring combined with a very sensitive magnetic detector system, i. The strength, the three dimensional localisation and orientation of the magnetic source can be reconstructed from these measurements as a function of time [ — ]. SQUIDs have been employed for the in-vivo characterisation of the oesophageal transit, the gastric and the intestinal behaviour of capsules [ , ] and tablets [ ].

These studies showed that the in vivo disintegration of capsules in the stomach correlates very well with the disintegration behaviour measured in-vitro [ ]. However, they further observed in several cases in different volunteers that a capsule disintegrated in the small intestine and not in the stomach as intended. Similar studies were performed by applying multisensor alternate current biosusceptometry ACB to analyse the in-vitro and in-vivo disintegration performance of magnetic tablets in the human colon under normal physiological conditions [ ].

These measurements enabled the quantification of the in-vivo performance by the gastric residence time, small intestinal transit time, orocaecal transit time and the disintegration time of magnetic formulations in the human gastrointestinal tract [ — ]. Cora et al. Traditionally the key parameter to assess the performance of a drug is to study the dissolution kinetics.

As discussed above, dissolution might occur simultaneously with disintegration, though in the majority of cases one refers to the dissolution afterthe disintegration. However, disintegration and dissolution are interlinked and both processes have to be considered when one assesses and further wants to improve drug performance.

Optimising the drug performance by modifying the disintegration processes is specifically important for the increasing number of poorly-soluble drug candidates, where dissolution is mainly the rate-limiting step in drug absorption [ , ]. This section focuses on results from dissolution studies related to immediate-release tablets, which are readily impacted by disintegration. Traditional dissolution testing cannot be used to gain insights about the early dissolution events acting in parallel to the disintegration as these methods suffer from delayed response.

The most promising technique to study early dissolution is ultra-violet UV imaging providing temporarily and spatially resolved absorbance maps. The authors demonstrated that the dissolution of amlodipine besylate was faster from the amorphous form than from the crystalline forms. It is well known in pharmaceutical sciences that the dissolution rate can be optimised by changing the solid-state properties of the drug.

This includes the use of high-energy solid forms e. These approaches often result in metastable or even unstable forms of the API, which might convert to a thermodynamically more stable form [ ] during disintegration. Therefore, it is of great importance to better understand the affect of a dissolution medium on the solid-state properties of the drug [ — ]. They demonstrated that sodium naproxen Fig. Studying the fast dissolution process of sodium naproxen in 0.

Red colour indicates high absorbance and the contours represent isoabsorbance lines. To date research focused on the in-situ analysis of modified-release tablets, where non-destructive methods including near-infrared NIR Near-infrared spectroscopy [ 7 , ], Raman spectroscopy [ , , ], UV imaging [ , , , ], infrared imaging [ , — ] and MRI [ , , ] have been used very successfully.

However, there is still a lack of understanding immediate-release tablets and solid state transformations occurring when the dissolution medium comes in contact with liquid. The last sections highlight that significant progress was made experimentally in recent years to measure and better understand disintegration phenomena.

In order to transform the design of solid dosage forms from an empirical art to a rational science it is essential to quantitatively describe the relationship between structure, formulation and disintegration behaviour. Mathematical models that accurately describe the physics of the process are required to reliably predict tablet disintegration, dissolution and eventually the drug release profile.

In order to achieve this the models not only have to describe liquid ingress, swelling, strain recovery, dissolution as well as disruption of particle-particle bonds Fig. This is clearly a highly complex problem. The transport kinetics of a range of formulations and physical properties were modelled by Yassin et al. This semi-empirical model was previously used to study drug release kinetics [ — ] and can be expressed by. In the study by Yassin et al.

Based on the value of the exponent m the mass transport mechanism is assumed to be dominated by a pressure gradient typically referred to as Darcy flow , by an activity gradient case II relaxation or can be regarded as a combination of both anomalous diffusion [ 77 ]. As expected, Darcy flow characteristics are dominating at higher porosity as faster liquid penetration can take place given the larger amount of available pore space.

Exponent m see Eq. The liquid penetration of the respective samples are shown in Fig. Error bars represent the standard deviation. An equation for the liquid penetration can be analytically derived by neglecting the effect of gravity and using the Young-Laplace equation Eq. As a note, the capillary radius R c ,0 is the pore radius, which is seen by the liquid meniscus. If the liquid penetration is driven by capillary action, it can also be modelled using the Hagen-Poiseuille Eq.

Combining both equation gives an expression for the liquid front L in the porous medium, which is known as the Washburn equation [ ]:. The Washburn euqation is commonly used across a range of scientific and engineering disciplines to study penetration kinetics in porous media. One of the first applications of the Washburn equation in the pharmaceutical science was presented by Nogami, Hasegawa and Miyamoto [ 36 ].

They slightly adapted Eq. Comparing the power law Eq. However, these simple models were developed for rigid systems and do not account for any swelling of the matrix during hydration. As discussed in the previous sections, swelling is not only very common for pharmaceutical formulations but it is often essential for successful disintegration to take place.

Swelling results in a dynamic change of the intrinsic permeability, porosity and pore radius. Schuchardt and Berg [ ] adapted the Washburn equation by assuming a linear decrease with time of the pore radius in the wetted area of a porous medium a composite of cellulose and superabsorbent fibres. They considered R h as the time-dependent effective hydrodynamic radius behind the advancing liquid front. The modified Washburn equation is thus expressed by.

Following the approach by Schuchard and Berg, Masoodi et al. They derived the following equation for the liquid penetration:. This model allows to analyse the time-dependent permeability, porosity and pore size and thus it provides an insight into the microstructural changes during the hydration of swelling porous media.

However, it is important to point out that these models describe the swelling process only during the transient liquid penetration and do not provide any details about the subsequent swelling once the powder compact is fully hydrated. Experimental data of samples that contain a large amount of crosslinked polymer or microcrystalline polymer indicates that typically two phases of swelling are taking place successively in such materials: initial rapid swelling due to liquid penetration and secondary swelling due to the disentanglement and diffusion of the polymer macromolecules into the hydrating solution [ 45 , 46 ].

The second, much slower, phase of swelling appears to be asymptotic in nature and can be modelled using the Schott model [ 45 , 46 ].

The original Schott model was developed to describe the water uptake in semicrystalline polymers such as gelatine and cellulose expressed as a mass uptake in grams of absorbed solution per grams of solid matrix. A swelling is a material constant that can be determined experimentally by linear regression. The combination of the Schott model Eq.

The swelling of individual MCC particles causes a decrease of the average pore radius, which reduces the porosity of the powder compact as time increases. Since the permeability is also a function of the pore radius, it decreases over time as well. These simulations clearly emphasise the complex interplay between the different microstructural properties of a tablet, which cannot be examined in such detail on the basis of experimental data only. However, newly developed models have to be validated by experimental data on the basis of characteristic measurable disintegration phenomena, i.

Therefore, it is only through a combination of modelling approaches and in-situ monitoring that fundamental insights of the disintegration process can be gained. A modified Carman-Kozeny see Eq. Using a different approach, swelling and the resultant detachment of particles was modelled by Caramella et al.

Their model treats the progressive tablet expansion alongside an associated layer detachment process Fig. A similar model was already introduced in the 60s by Nogami, Hasegawa and Miyamoto [ 36 ] to study the liquid penetration into aspirin tablets. In the models of both groups the assumption is made that the disintegration of particles occurs only in layers parallel to the surface of the largest area of the tablet i.

In the model from Caramella et al. Modelling the detachment of particles during disintegraton. Caramella et al. Peppas and Colombo [ 40 ] later expanded this analysis and provided a model which considers fluid mechanical phenomena, the changes in pore structure during the initial water uptake as well as the swelling of the disintegrant:.

C 0 describes the initial stresses of the tablet and the potential change of stresses when water fills the pores. C c and C d are indicative for the relative importance of the convective and diffusive portion of the disintegration phenomenon. The model was verified using the apparatus presented in Fig. The models by Caramella et al. In order to model the rupture of the inter -particle bonds, one needs to consider the formation of cracks within the tablet [ ]. Cracks may propagate in the direction of fluid movement through the tablet until the critical crack length is reached where the dosage form fractures.

This process is conceptually similar to the more well understood mechanisms in other fields of wet granular matter pendular, funicular, capillary and slurry states.

Therefore, models developed in these fields [ — ] could be used in future to quantitatively describe the last phase of the disintegration process and to determine the critical stage when the liquid bridges rupture and the tablet completely disintegrates. The history of dissolution research started in the 19th century when Noyes and Whitney conducted the first dissolution experiments [ ].

The authors concluded that the rate at which a solid dosage form dissolves is proportional to the difference between the instantaneous concentration c t at time t and the concentration of the saturated solution c S. This statement can be expressed as. Nernst [ ] and Brunner [ ] carried out further experimental studies and addressed the physical meaning of the constant k as defined by Noyes and Whitney. From looking at the Nernst-Brunner equation, it is immediately obvious that the kinetics of drug dissolution is affected by intrinsic and extrinsic factors.

The intrinsic properties of a drug substance that may influence the dissolution include crystallinity, polymorphism, hydration, particle size and particle solid surface. The total surface area of the sample exposed in the solvent is one of the main aspects that influences the dissolution rate. In fact the dissolution process can be accelerated by increasing surface area and decreasing the particle size. Furthermore, hydrodynamics and composition of the dissolution medium e.

The Noyes-Whitney and Nernst-Brunner equations provided the basis for understanding drug release kinetics; even though they do not address all mechanisms involved in the drug release process. Wilson et al. The authors considered disintegration and dissolution in terms of reaction rates enabling the combination of both processes.

As summarised by Siepmann and Siepmann [ ], besides the dissolution process itself the drug release of oral dosage forms includes the diffusion of water into the system, drug diffusion out of the device, polymer swelling, matrix former erosion, osmotic effects and various other phenomena. These processes occur in sequence but differ in terms of action time.

The dissolution behaviour of controlled-release dosage forms was studied in much more detail by developing mathematical models and applying a range of non-destructive methods. A number of studies described the drug release kinetics by combining experimental data and theoretical models [ , ].

It was shown that the rate of diffusion into and out of a tablet can be described by a semi-empirical equation, i. Another semi-empirical model is the Peppas-Sahlin equation [ ] given as. Similar to the discussion above for porous systems, both the power law and the Peppas-Sahlin equation are used to differentiate between, here, Fickian diffusion and case II relaxation; Fickian transport relies on a concentration gradient and case II transport on an activity gradient.

In analogy to our discussion above the power law can also be used to describe an anomalous diffusion containing both Fickian and case II characteristics. Siepmann and Siepmann [ , ] described models for a broad range of controlled-release devices including reservoir and matrix systems, which may or may not exhibit an initial excess of drug, and that are valid for a range of geometries: slabs, spheres and cylinders.

Only the combination of models describing the liquid penetration, swelling, the formation of cracks and the break up of the tablet as well as the dissolution of the disintegrated particles will lead to a sound understanding of the disintegration and dissolution processes of immediate-release tablets.

For more than 15 years there has been a concerted effort in the pharmaceutical community to improve the quality and consistency of pharmaceutical products by introducing a paradigm shift to how we innovate higher quality medicines. This has included the development of concepts such as QbD and process analytical technology PAT initiatives that aim to actively encourage in an in-depth understanding of processes and product characteristics that could be used to implement suitable control strategies to pharmaceutical processing.

Significant progress has been achieved and advanced analytical methods are now routinely deployed to test chemical and physical quality attributes throughout drug product development and manufacturing. However, not all areas of process understanding and quality testing have been equally transformed by this development.

Even though there is clearly a longstanding interest in improving the rational understanding of the complex disintegration process that is well documented in the literature and innovative methodologies have been proposed to better measure the phenomena involved there has been no breakthrough yet in developing robust quantitative models of the process that could be used for the rational design of disintegrating dosage forms.

We believe that one of the factors that presently limits the development of a better understanding of the fundamental importance of disintegration can be found in the anachronistic disintegration test prescribed by the pharmacopoeia.

Not only does the test fail to provide any insight into the physico-chemical changes that govern disintegration but, by defining the disintegration time as the time after which the last of six tablets fully disintegrates, the test result makes it hard, if not impossible, to resolve the subtle variations in microstructure that are critical for the process.

The test was developed more than 80 years ago and the testing protocol has not changed very much over the years yet a large range of novel rapidly disintegrating formulations, dosage forms and new excipients have been developed in the interim and with this development the quality control requirements have changed. Whilst the disintegration test has served an excellent purpose since its inception it had the unfortunate side effect that too many pharmaceutical scientists now habitually assume that the disintegration test is a suitable test to investigate disintegration.

It is important to highlight that this is not the case — it is a very good test to document compliance with a particular validation protocol required by the pharmacopoeia but it was never designed to help with the understanding of the complex process itself.

Besides the analytical testing procedure itself we have identified a range of scientific challenges that need to be addressed before mathematical models will be available that can be used as confidently to predict disintegration as it is possible for dissolution today.

The role of the microstructure of the porous matrix on the disintegration mechanism and kinetics is clear and it is absolutely clear that subtle variations in processing parameters result in significant changes for the disintegration process. A detailed understanding of the interplay between process parameters, microstructure and disintegration behaviour will be critical for high quality immediate-release products manufactured by continuous processing with active feedback loops controlling the process.

Overall, the design of immediate-release dosage forms will greatly benefit from quantitative physical models of disintegration and we hope this review will stimulate fruitful discussion and encourage further work in this area to achieve this aim in the near future.

We would like to acknowledge the U. The liquid penetration in highly porous immediate-release tablets is driven by capillary forces. Examples: "synonyms: fade out". Compare words:. Compare with synonyms and related words: disintegrate vs dismember disintegrate vs dissolve compost vs disintegrate decay vs disintegrate disintegrate vs dissolve.