A modified release drug is one which is consumed by mouth but is not immediately released. Instead, it is subject to a planned and measured delay in release, and is said to have sustained release, controlled release, timed release, prolonged release, or delayed release. The advantage of such a formulation is that it acts over a longer duration, thus avoiding the need for repeated daily doses.
In sustained release, the initial release of the drug occurs rapidly to achieve quick action, but subsequently takes place at a more or less constant rate over a long time, both of which are predefined parameters. This keeps the drug concentration in the plasma steady without excessive side effects.
Controlled release focuses more on providing a steady concentration to achieve therapeutic effects at the designated site of activity. Depending on the purpose and properties, sustained release can be classified as controlled release.
The most frequently used capsule material is hydroxypropyl methyl cellulose, a hydrophilic polymer which swells in water. This is due to the entry of water molecules into the capsule which dissolve some of the drug. The soluble drug concentration is now changed, resulting in diffusion of the drug through the hydrated gel of the capsule. Once the capsule has dissolved completely over time, the small amount of remaining undissolved drug is released all at once.
In this experiment, a medication used for the relief of heartburn was studied, being available over the counter, and having a timed-release formulation. Several capsules were used in each experiment, and each was first divided into equal halves so that the contents in bead form could be removed.
The drug dissolution was then measured on each of the capsules using the Microtrac Sync combined particle size and image analysis device. The changes in size and shape were measured, as well as how well the instrument could identify how the drug dissolved.
Data and Results
The beads were mixed in Isopar G, a medium in which water-soluble particles do not dissolve. Figure 1 is the printout of the size of the measured beads, obtained by Sync diffraction. Figure 2 shows the result of mixing the beads with additional water and agitation by the Sync circulation system, taking measurements at intervals of 45 seconds over a period of four minutes.
The figure shows that small particles were immediately released, as seen by the second peak. These particles of 0.25 µm to 2 µm size are easily picked up by the Microtrac Sync technology which relies on laser diffraction that is capable of resolving particles up to 0.010 µm or 10 nm. At a later time the finer peak reduces in amplitude, until, as Figure 3 and 4 show, complete drug dissolution has taken place.
On the other hand the blue curve shows larger particles only, corresponding to the four-minute period of mixing. The diffraction data also reveals the transmission value and signal (which are inversely related) which enables the drug disappearance to be followed. When more light is transmitted, it shows that not many particles are passing through the Sync circulation system, leading to persistence of much of the original intensity of the laser.
The image analysis shows the same pattern. Figure 5 shows how the volume and number are distributed for the area-equivalent diameter (Da), in columns 1 and 2. When the particles are very fine, the volume is small and the number is low, as might be expected from the relationship of volume and number. This is seen in the graph in Figure 6 as well as the scatter diagram in Figure 7. The latter confirms this bimodal distribution based upon such a relationship, through the scatter plots for volume and number distribution for the image range scanned. Thus, the number scatter diagram shows a second peak from the image tabular information, but not the Da volume diagram.
The “Search” function of the Sync image analysis software yields several areas of data. For instance, if one searches for all particles with more than 0.9% sphericity, they are found to make up 93.85% of volume and 87% (3987/4577) of the total particle number. Searching for particles over 100 µm in volume shows that these comprise 99.98% of volume but 21% of particle number (993/4577).
Again, a search for particles which are over 100 µm in size and have a sphericity of over 0.9 yields a figure of 93.84%. This type of data output often serves as a useful point to generate specifications that are essential for manufacture or quality control of a product.
Figure 8 shows particles that approach the smallest visible range at less than 2-5 µm. The shapes of the particles resemble those of the particles on the larger side. The finest particles picked up by laser diffraction are not capable of being analyzed by the Sync software.
Some of the particles are not round, but may have been subject to attrition or disrupted in some way, as indicated by the decreased ratio of width to length. Only 0.45% of the volume is composed of particles below 100 µm in size.
The use of a technique which measures the particle size both by diffraction and image analysis yields important data which is vital in setting limits and goals for both manufacture and quality control. Both these features of the Sync instrumentation help understand issues with a particular process or what is happening in research and development. They use different technologies and have somewhat differing abilities.
Diffraction provides results based on how a cloud of particles acts when passed through a laser beam. On the other hand, image analysis depends on acquiring photographs of the particles under study, followed by calculations of single particle properties based on the geometry of these images. This difference is an advantage because they complement each other by simultaneously measuring the same phenomenon in two different ways, allowing for synergistic measurement.
Table 1. shows how it is helpful to analyze particle size and volume in two different ways. The overlap of size between two sets of particles resulted in the detection of particles of similar range by both techniques. The larger peak of particle size shows volume distributions to be similar as long as the measurable range is similar.
The disparity in volume and number distribution between the two techniques stems from their different size measurement capabilities. Image analysis does not pick up all the particles which laser diffraction can detect, and thus only the latter shows the peak that completely represents the finer particles. The larger particles are much lower in number but they contribute most of the weight of the product.
The presence of the large and small particle peaks shows that there is a gross difference in particle size which could result in this type of separation during transport of the mixture. This is especially important with spherical particles which separate with ease compared to other shapes. The ability to detect a particle peak due to very fine particles by laser diffraction is valuable for materials which are meant to be absorbed in the body, because size is closely related to expected absorption kinetics.
Overall, the combination of these two methods in the Microtrac Sync gives a synergistic effect which allows the sample to be characterized with much greater clarity than either method could achieve alone.
This information has been sourced, reviewed and adapted from materials provided by Microtrac, Inc.
For more information on this source, please visit Microtrac, Inc.