10 Essential Benefits of a Reliable Softgel Capsule Hardness Tester

What’s a softgel capsule hardness tester? Soft gelatin capsules need to undergo elasticity testing before packaging. This is where the tester is required, and not any ordinary tester.

The manufacturers of the capsules need a reliablesoftgel capsule hardness testerto ensure that their products have passed the set industry-standard quality before they release the products to the consuming public.

The result will indicate whether or not the capsule has the go-signal to be packed. This way, repeated failure during packaging, which could mean additional costs to the manufacturer, can be prevented.

Gelomat aims to obtain the highest quality standards in testing gelatin capsules

More about Soft Gel Capsules

There are rules set regarding the use of agelatine hardness testerin capsule products. Typically, the number of tests required depends on the capsules’ unit dose. However, it offers many other benefits that this article will look into.

But first, here’s what you need to know about soft gel capsules. These products are prevalently used in medicines, mineral supplements, and vitamins. The capsule or microcapsules are packed with active ingredients inside to protect the product from a variety of factors.

These active ingredients are released by diffusion, melting, dissolution, or rupture once a person places the capsule into their mouth. How slow or fast the active ingredients will be released depends on the capsule wall’s strength.

Soft gel capsules, also called gel caps or gelatin capsules, are made from animal bone and skin collagen manufactured to make gelatin. There are also vegetarian or vegetable capsules made of cellulose, which use HPMC or hydroxypropyl methylcellulose as the main ingredient. However, it is more cost-efficient to manufacture gel caps, which is why it is more extensively used than the other type.

There are two kinds of gelatin capsules – soft shell and hard shell.

Soft shell capsules have oils or use active ingredients suspended or dissolved in oil.

Hard shell capsules have miniature pellets or dry, powdered ingredients. They are made in two halves: One of the halves contains the medicine, and the other half has a bigger diameter, and is used as a cap to seal the capsule.

All about the Gelomat Capsule Hardness Tester

Gelomat is a device used to test capsule hardness automatically. It works for both soft get and regular capsules. It is capable of performing the hardness test on edible gelatin, plasticine, gelatin capsules, and other materials. It comes with a standard testing head, but other accessories can be added to upgrade the device and boost its efficiency.

Gelomat aims to obtain the highest quality standards in testing gelatin capsules. It is developed using the latest R&D technology and a state-of-the-art system. The device can be equipped with testing heads that vary in their load capacity: 0-2N and 0-20N. The operator can choose from the heads and interchange them as needed by the requirements.

Top Benefits of a Reliable Softgel Capsule Hardness Tester

1. Non-destructive solution

Gelomat provides a non-destructive solution for testing the hardness of soft gel capsules. Aside from soft gel capsules and gelatin, it can also measure the resistance and hardness of agars, paintball, play dough, and more. The digital measuring systems and the device’s unique design ensure the most reliable and highest level of measuring precision.

Aside from using the standard measuring head from 0-2N or 0-20N, the operator can opt to attach Centrofix or Rotofix. Centrofix is a sample fixture that is operated manually. Rotofix is a positioning device that operates automatically. The user can perform functions with the help of the software, including creating batch folders, viewing histograms, storing data, analyzing the results, and more.

Why all the fuss in testing soft gel capsules? The encapsulating process is meticulous, but it focuses on the form. It ensures the capsule is formed and can hold the filling. Once the capsules have undergone all necessary steps to attain their final form, the testing is done.

Here’s a look at the steps on how to make soft gel capsules:

A 24-inch in diameter stainless steel drum slowly revolves as the warm liquid gelatin is poured.

The drum is exposed to the compressor’s flow rate of 400 cubic feet per minute with air temperature up to 590F at 20 percent RH.

As the drum continues to revolve, the gelatin is congealed with the cool, dry air until an elastic and tacky band rolls over the other end.

The thin band is what forms the capsules. The process is done automatically.

The capsules are filled with the manufacturer’s products, such as vitamins, medicine, supplements, and more.

The filled capsules are sealed and dropped into a tray.

The filled capsules are still moist and soft, so they are transferred to chambers or drying drums.

Drying time varies on many factors, including the time needed to remove the moisture, the number of capsules, and the size of the capsules.

This is how meticulous it is to form the soft gel capsules. The temperature of the air that the drum gets exposed to during the pouring process is crucial since it can cause the gels to become too brittle or set too fast. Both these results can stop production and repeat the process from the start.

When the air velocity is too high, the thickness or thinness of the gel capsules won’t be consistent. On the other hand, when it is too low, and the humidity and air temperature are too high, the gelatin will find it hard to solidify.

The temperature of the environment needs to be continuously controlled during drying time. The ideal humidity level is at 20 grains per pound of air and a dew point of 25° F.

When the capsules have completely dried, they are tested using a softgel capsule hardness tester, such as Gelomat. Even then, the number of capsules that will eventually be sold to the market will depend on the test results. This ensures that the preserved inventory is of value and won’t compromise the name of the manufacturer.

Why is it important for the device to be highly reproducible? The capsules are tested in batches, and each one in the batch must show similar characteristics and hardness to the rest.

2. The tester was built for durability and accuracy

This gelatine hardness tester was developed with the highest standard accuracy available for a German-manufactured device. It is also highly reproducible.

Why is it important for the device to be highly reproducible? The capsules are tested in batches, and each one in the batch must show similar characteristics and hardness to the rest.

You wouldn’t want the consumer to observe the differences and conclude that the softer ones are expired, or they were given inauthentic items. Only when the capsules are highly replicated can the highest degree of reliability be attained.

In science, reproducibility is the final and third phase of precision testing. To obtain stability, a marker system is selected, depending on the product being tested. In testing gelatin capsules, the dry plasticizer is the suitable weight ratio.

The ratio of dry gelatin to water is 1:1, and the dry gelatin equals 0.4-0.6:1.0. When the weight ratio obtained is 1.8:1, this means that the shell is soft. The weight ratio between the plasticizer and gelatin needs to be 0.3:1.0 for the capsule to be at its hardest form.

3. Suitable for different industries – pharmaceutical industry

A tablet hardness tester is primarily used in the pharmaceutical industry. This laboratory testing determines a tablet’s structural integrity and breaking point. It determines how it changes during handling, packaging, transportation, and storage. The shape determines a tablet’s breaking point.

This kind of tester has been around since the 1930s. But it was only patented in 1953 by Robert Albrecht and called the Strong-Cobb tester. At the time, it was utilized as an air pump.

The problem with the older models of the testers was inconsistency in the results. This is what the newer models, such as the Gelomat, have surpassed.

This is made possible by including the following features in this well-known device:

Full integration of automatic measuring process

Hysteresis function

Gives a high rate of testing efficiency and the highest level of accuracy

Customized holding fixtures

Convenient and fast data transfer through a USB port

User-friendly system designed to meet repeatability and the highest standards of accuracy

Auto-correction feature

Digital display shows when values obtained are below or above the limit value

The digital display unit is capable of various functions, including measuring time and range

4. Suitable for different industries – paintball industry

What’s the use of a hardness tester in the paintball industry? Similar to what needs to be obtained in capsules, paintballs also require a repeatable and reliable method of testing ball seizers, barrels, and markers. The testing system needs to ensure accuracy, repeatability, and simplicity.

In this industry, it is crucial to isolate and define the independent and dependent variables that affect the trajectory of a paintball. The accuracy of the ball highly depends on its quality. You can only shoot the ball straight if it is not swelled, seamed, or dimpled – factors that the tester takes note of and gets rid of.

Aside from the ball quality, the barrel’s hardness also determines the internal finish’s longevity. The holes of the barrel also need to have sufficient angle and size. For the filling, many manufacturers use compressed air because they find it more reliable, and offers a higher accuracy rate than CO2.

5. Suitable for different industries – cosmetic industry

There are many products in the cosmetic industry that will benefit from undergoing hardness testing. For one, a cosmetic foundation goes through the test to ensure that it is hard enough when pressed and qualifies the set standards of R&D and quality control. This is typically done using a tester that utilizes software, cable, test stand, and force gauge measurements. The tester has mechanical properties, including the peeling force, compression, and tension.

The hardness tester can also be used to ensure the quality of cosmetic products, including lipstick, brow or lip pen, and wax and cream products. More than the hardness, the industry relies on the results of the texture test of the products. They have to make sure that the cosmetics feel good on the skin before releasing them to the market.

6. Tests materials for tension and compression

When soft gels undergo testing, the capsule’s wall strength is quantified to determine its rupture point. It also determines the weakness of the seal or the film of the gelatine. The testing is done to simulate the factors that might cause the capsule to burst before it reaches the consumer.

Gelomat applies a compressive force to the capsules to gather data on whether or not they have passed quality control. The device tests the wall strength of the capsules, if they are enough to carry the capsule’s form even after being subjected to external forces.

The purpose of the device is to ensure that no leaking capsules get into the hands of consumers. This results in a higher level of confidence of consumers in the manufacturers and an increased rate that they will buy again.

Hardness testing is only among the many tests that products, such as capsules, go through to implement quality control. The same is true for paintballs and cosmetic products. All these items intended to be bought or consumed by consumers have undergone a series of tests before they are packaged and sold.

For soft gel capsules, each batch undergoes batteries of tests to determine that they meet the standards according to how they are advertised and acceptable for consumption.

7. Uses the latest in technology

Unlike the older models, the recently developed hardness testers, such as the German manufactured Gelomat offer integrated value, efficiency, and the latest in patented technology. Gelomat can be used as a meat hardness tester, cream hardness tester, butter hardness tester, and more. This shows how serious manufacturers are in ensuring that their customers get the best products.

Gelomat employs accurate digital measuring systems and unique design to make the process easier to do without sacrificing the results of the tests. Gelatin capsules undergo an automatic measurement for their hardness through a system that can be trusted to obtain optimum repeatability and accuracy.

The Gelomat system is one of the only systems in the world capable of the ultimate flexibility through the development of custom fixtures and anvils to meet clients unique testing requirements. This makes the Gelomat system a one-of-a-kind solution package.

8. Making it easier to quantify hardness in tablets

Solid tablets are the most common form of dosage used in pharmaceuticals. The hardness of the tablets comprises the specifications of the product’s quality control and criteria for product development.

The tablet hardness tester needs to obtain quality results from the product, meaning that each tablet is not too soft and not too hard.

When a tablet is too soft, it may lead to early disintegration once taken by the patient. It can happen as a result of weak bonding. Additionally, a tablet that is too soft can break or chip during packaging, coating, and other manufacturing stages.

On the other hand, when the tablet is extremely hard, it can lead to the improper dissolution of proper dosage once a patient takes it. The problem may be rooted in too much bonding potential between excipients and active ingredients.

Testing the tablet’s hardness will quantify if the product is consumable and has passed the highest quality standards. However, it also has to contain all mechanical properties needed for optimized results. The manufacturer needs to see that the product used the right composition of the ingredients, the nature of active ingredients, and the binders used. They have to control these factors while still in production to increase the chances that the final tablets will pass the hardness test.

9. Ensures strict compliance to the latest industry standards

When it comes to gelatin capsules, the finished products need to undergo tests. You may already have heard of terms such as capsule hardness tester orgelatine hardness tester.

The capsules undergo a number of tests to comply with the regulatory requirements and compendial standards. The results of the tests will determine if the batch has passed for its intended usage and marketing.

10. Gain public trust

Why are these tests necessary? These products heavily rely on consumers’ trust. Leaking capsules can have a negative impact on how people view the product and all other products from the same manufacturer.

This is why it is crucial that the defective capsules do not reach the market; hence, the manufacturers use a softgel capsule hardness tester to ensure that all the products they will release in the market won’t compromise their name.

Final Thoughts

Your quality control facility will gain many benefits from using the softgel hardness tester, but you have to rely on the tested and quality devices. This is what Bareiss is known for, the company that has been committed to technology and innovations since it was founded in 1954.

Testing: How Leak-Proof are Your Capsules?

Leaking gelatin capsules diminish consumer confidence in the product and the manufacturer. To prevent defective capsules from reaching the market, you must develop tests to identify them. One approach is to use a texture analyzer instrument that applies tensile and compressive forces to gelatin capsules to confirm they have sufficient wall strength to withstand external forces during manufacturing, storage, packaging, and transport. 

When formulating a capsule drug product, it’s important to know whether the fill—both the API and excipients— is compatible with the gelatin shell, which comprises a mixture of water-soluble proteins. Any substances that contain aldehydes (e.g., formaldehyde) can cause the gelatin to cross-link, with lysine residue within and between gelatin strands. This stiffens the gelatin structure and slows its disintegration. Learning how a fill will interact with the gelatin shell’s water content is also important. A highly hygroscopic fill, for instance, may absorb water from the shell and cause it to become brittle and more prone to breakage. 

A texture analyzer quantifies the mechanical strength of hard gelatin capsule shells so you can assess how different fills affect capsule strength and stability. It does so by imposing controlled mechanical conditions on a sample and then quantifying the resulting behavior. How the samples respond relates directly to their physical characteristics and provides a real-life indication of their internal structure. 

A texture analyzer operates in tension or compression mode and can perform cyclic testing, in which it imposes a deformation action multiple times. The instrument measures load force, usually in grams, and associates it with capsule deformation. The results are then presented in a graphical format as force versus time or as force versus distance. Various textural parameters can be at work during deformation and it’s possible to observe them in the force-deformation curve that the test generates. In the last 40 years, many academic studies that used texture analysis have correlated these behaviors with their sensorial characteristics. 

Capsule-Loop Tensile Test 

Equipping the texture analyzer with a capsule-loop tensile fixture, as shown in the photo above, enables you to compare the mechanical strength of empty capsule shells. In practice, the fixture’s two thin rods are inserted into one half of the capsule shell, usually the cap. The lower rod is then anchored to the instrument base, while the upper rod is attached to the drive mechanism of the analyzer. The drive lifts the upper rod at a steady rate, typically between 0.1 and 1.0 millimeter per second, stretching the capsule shell a defined distance. In some cases, the test causes the shell to rupture. 

Compression Test 

A texture analyzer can also measure the compressive strength of a soft gelatin capsule (softgel) using two test methods. In the first, a probe 36 millimeters in diameter is used to quantify the seal strength (Figure 2) and in the second—a penetration test—a 2-millimeter cylindrical probe determines the softgel’s rupture point. The two tests not only identify weaknesses in the softgel’s strength, they simulate the circumstances under which the softgel could burst during packaging or transport. When measuring the seal strength of any capsule—hard or soft—use a compression probe whose diameter is larger than the capsule and orient the seal perpendicular to both the probe and the applied force. See the photo below. Table 2 lists the results of softgel hardness tests.

Gel Strength Test 

Gelatin is used in many industries and in many different applications, and in nearly all cases, both the gelatin manufacturer and the end-user measure gel strength, which indicates its effectiveness. Gel strength depends largely on bloom strength. The photo on the next page shows a bloom jar with a gelatin sample ready to be tested. 

Using a texture analyzer equipped with a standard bloom probe, bloom bottles, and a gelatin bath, you can perform simple tests and quickly and accurately determine gel strength, which is measured as the force required to deform the gel over a specified distance.

A texture analyzer can be used to quantify the gel strength of gelatin according to the British Standard Method, “Sampling and testing gelatin” (BS757: 1975) or by using standards from the Gelatin Manufacturers Institute of America (GMIA) or the Gelatine Manufacturers of Europe, which in 1998 adopted the GMIA standard. As a result, all current methods specify the use of a flat-faced cylindrical probe 12.7 millimeters in diameter with a sharp edge. (The European method specified a probe with a small radius instead of a sharp edge.) 

This method can also be used with other capsule shell materials, such as HPMC. When testing samples with high mechanical strength, consider using a load cell with a larger capacity. Likewise, for samples with a highly elastic component, you may need to lengthen the test distance. 

Kokkuvõte 

By identifying key characteristics that affect the finished product, texture analysis is an integral part of R&D, process optimization, and production. It helps guide your choices during the initial stages of development and provides at-line process control. By setting high and low limits of acceptance, texture analysis enables you to optimize manufacturing and reduce waste. 

Challenges of Dissolution Methods Development for Soft Gelatin Capsules

Noyes and Whitney first documented the study of the dissolution process in 1897 as a field of physical chemistry, which later was mimicked in pharmacy due to its importance in drug administration [74]. The dissolution of solid dosage forms attracted attention as the realization of the importance of drug dissolution concerning bioavailability was identified in the 1950s with the understanding that only dissolved drugs can diffuse through the human body [74,75,76,77,78]. Poor drug solubility and low dissolution rates potentially lead to insufficient availability of the drug at the site of action and subsequent failure of the in vivo therapeutic performance. This is independent of the fact that the drug could be an ideal structure for the target site. Essentially, if the drug is too insoluble, it can never reach its target site, and it will be of no therapeutic relevance. Characterization of the dissolution of a drug from a given dosage form is critical for the successful development of a drug product. This section discusses the current state-of-the-art of SGCs dissolution and various practical concepts of developing dissolution methods for SGCs.

Dissolution testing is an official test used for evaluating the rate of drug release from a dosage form into the dissolution medium or solvent under standardized conditions of liquid/solid interface, temperature, paddle speed, or solvent composition. Dissolution testing has become important in measuring the in vitro rate and extent of API release from different dosage forms, including SGCs. Dissolution can be described as a process by which molecules of a solute (e.g., API) are dissolved in a solvent to form a solution. The in vivo effectiveness of a dosage form depends on its ability to release the drug for systemic absorption. SGCs dissolution goes through three main steps, the first one being swelling and rupture of the gelatin shell, followed by release and dispersion of the fill material, and finally, the dissolution of the active ingredient(s) in the dissolution medium ( ). These processes occur in series, and thus the slowest step determines dissolution rate of the SGCs. The slowest step in this case controls the overall rate and extent of drug absorption. However, this varies from drug to drug. For poorly soluble drugs, especially BCS II and IV, their dissolution will be a rate-limiting step in the absorption process. On the other hand, for drugs that have high solubility, their dissolution will be rapid, and rate and extent of absorption can be affected by other factors, e.g., membrane permeability, enzymes degradation in the GIT, or first pass metabolism.

A critical requirement for drug products is that they release the APIs in vivo at a predictable rate [ 9 , 82 , 83 ]. The kinetics of drug release follows the release mechanism of the system, such as diffusion through the inert matrix, diffusion across the gel, osmotic release, ion-exchange, or pH-sensitive delivery systems. Among the various mechanisms involved in API release, diffusion is the principal release mechanism, and it takes place at varying degrees in every system. Solute release models in physical chemistry preceded the development of drug delivery systems by many years [ 77 , 78 ]. In 1961, Higuchi introduced a mathematical model of drug release for diffusion-controlled systems [ 84 ]. The author analyzed the release kinetics of an ointment, assuming that it is homogeneously dispersed and is released in the planar matrix and the medium. According to the model, the release mechanism is proportional to the square root of time [ 85 ]. This model is recommended for the initial 60% of the release curve due to its approximate nature. In late 1969, Wang published an article considering the two independent mechanisms of transport, Fick’s law, and polymer relaxation on the molecules’ movement in the matrix [ 86 ]. Then, Peppas, in 1985, introduced a semi-empirical equation, power law, to describe drug release from polymeric devices in a generalized way [ 87 , 88 ].

Another concept that needs to be introduced here is the drug release phenomenon. Drug dissolution rates and drug release rates are quite different. Drug release refers to the process by which the drug in a drug product is released in the dissolution medium or at the site of absorption by diffusion or dissolution of a drug product. Depending on the physical form of the API in the drug product, the release of API may be slow or immediate. As described in the previous section, dissolution is a process by which molecules of a solute are dissolved in solvent vehicles as a function of time. On the other hand, the term “release” most often refers to a much more complex phenomenon. Release encompasses capsule dissolution as one of its several steps. Upon contact with the aqueous medium, water penetrates the soft gelatin shell and at least partially dissolves the API [ 81 ]. Then, the dissolved API diffuses out through the capsule shell due to concentration gradients. Furthermore, the gelatin shell might undergo significant swelling as soon as the critical water content is reached, which will result in the rupture of the shell, followed by dispersion and eventual dissolution in the release medium. Hence, several steps are involved in the process of releasing the API from SGCs drug products, with only one of them being drug dissolution.

The dissolution rate of a drug product in each solvent is defined as the rate of transfer of individual drug molecules from the solid particles into the solution as individual molecules, and it can be expressed as the concentration of dissolved API for a given time interval. The rate of dissolution can vary depending on the form of API, e.g., the amorphous form usually has rapid dissolution compared to crystalline forms of API [ 79 , 80 ].

Another important thermodynamic property in a discussion of dissolution processes is solubility, which may be expressed in several ways, including but not limited to molarity, molality, mole fraction, mole ratio, and parts per million. As an illustration, for the case of a drug molecule, consider an excess amount of solid that is exposed to the solvent phase at a defined temperature and pressure. In the equilibrium state, the number of drug molecules going into the solution equals the number of drug molecules which re-precipitate. Under these conditions, the solution is saturated with drug molecules and the concentration of dissolved drug under these conditions is defined as the “equilibrium drug solubility” (specific to the given temperature and pressure) [ 89 ]. It is important to assure that the solid phase present at the beginning of the experiment remains unaltered after reaching thermodynamic equilibrium during any solubility experiment. It is worth mentioning that, when particle size or the presence of additives, or the pH modifies the intrinsic solubility, this is usually reported as “apparent solubility” to distinguish it from the equilibrium value. In order to avoid the inconsistency in solubility data reporting, the size of filters used in the separation of dissolved drug particles must be stated.

However, the USP General Chapter , Disintegration and dissolution of dietary supplements, accepts a rupture test as a performance test of SGCs if the capsule content is semi-solid or liquid [ 92 ]. The rupture test is performed using apparatus 2, as described under General Chapter Dissolution , at a rotation speed of 50 rpm in 500 mL of immersion medium for a duration of 15 min. As per USP , the requirements are met if all of the SGCs tested rupture in not more than 15 min”. If 1 or 2 of the SGCs rupture in more than 15 min but not more than 30 min, the test is repeated on 12 additional SGCs: not more than 2 of the total of 18 capsules tested rupture in more than 15 but not more than 30 min. For SGCs that do not conform to the above rupture test acceptance criteria, the test is repeated with the addition of papain to the medium in the amount that results in an activity of not more than 550,000 units/L of medium or with the addition of bromelain in the amount that results in an activity of not more than 30 gelatin-digesting units/L of medium [ 92 ]. Almukainzi et al. [ 93 ] compared the rupture and disintegration tests of SGCs of amantadine, ginseng, flaxseed oil, pseudoephedrine hydrochloride, and soybean oil. Their data showed that neither rupture test nor disintegration test was advantageous over the other. However, rupture test reached the endpoint quicker compared to the disintegration test. In another study, Bachour et al. [ 94 ] evaluated the suitability of the rupture test for stability studies of SGCs containing oil-based oral multivitamins. Their study showed that the rupture test was sensitive to stability conditions, and that the commercial drug products passed the rupture test. However, all long-term stability samples failed the rupture test using tier 2 conditions. This indicates that the rupture test may be suitable for assessing the performance of some drug products, but this will depend on the properties of fill components.

The disintegration test is considered as one of the performance tests for the immediate release dosage forms [ 90 ]. As per the USP , disintegration is defined as “the state in which any residue of the unit, except fragments of insoluble coating or capsule shell, remaining on the screen of the test apparatus or adhering to the lower surface of the disk, if used, is a soft mass having no palpably firm core” [ 91 ]. The requirements of disintegration are met if all test units have completely disintegrated or if not fewer than 16 of a total of 18 units tested are disintegrated within a predetermined time period. This does not imply complete solution of the API or the drug product.

6.5. Practical Concepts of Developing a Dissolution Method

Dissolution testing is used throughout drug product development as an indicator of drug product performance. During formulation development, dissolution testing is used to demonstrate the release and uniformity of a dosage form in a simulated environment. Once the performance is established for the product, this information is used periodically during stability to determine if the characteristics of the product are changing in such a way that the product continues to or stops performing as required. Often, the performance of a drug product in dissolution shows physical behavior; however, it does not necessarily indicate performance in vivo. Therefore, correlation between dissolution and pharmacokinetic data can be used to demonstrate if dissolution testing has the ability to predict drug performance. This is referred to as establishing in vitro–in vivo correlation (IVIVC) [95].

The purpose of this section is to give an overview of the practical concepts of developing dissolution test methods for SGCs. It is important to understand that the dissolution of a product requires a number of physical changes to take place. Unlike other typical solid dose forms, SGCs must first reach the point where the integrity of the gelatin is compromised and the outer shell ruptures to allow release of the fill material. Following this, the fill components must disperse within the media to allow the active ingredients to either enter solution or distribute evenly throughout the media ( ). The challenge is that the capsule shell is very sensitive to its environment and can change relative to hardness, cross-linking, and seam integrity, which can all play a role in perceived dissolution changes when in fact they are changes in rupture time. Therefore, it is essential to develop a dissolution strategy that accounts for differences in the integrity of the capsule shell as well as changes in the fill material.

Dissolution methods development are labor-intensive processes even with careful technique and practice. It is important to invest time in developing a procedure that can be efficiently executed on a routine basis and repeated robustly. Dissolution tests are required by the Pharmacopeias to determine the release of the drug from the dosage form in an environment with a pH from 1.2 to 7.4. For example, USP [96] requires a two-step dissolution method for enteric-coated solid oral dosage forms that demonstrates coating integrity in an acidic environment, usually 0.1 N HCl, followed by exposure to a neutral pH environment, preferably with a phosphate buffer, where the first step of dissolution method provides information about the coating quality and the potential for coating failure. The United States Pharmacopeia (USP) and the U.S. Food and Drug Administration (FDA) provide guidelines on the development and validation of dissolution procedures [96,97]. Most of these guidelines are for solid oral dosage forms like tablets and hard gelatin capsules; however, one cannot extrapolate these methods to SGCs without proper assessment. The choice of dissolution method should be based on the dosage form and the fill characteristics of SGCs. shows the common USP dissolution apparatus used in dissolution testing.

 

Developing a discriminating dissolution test for SGCs requires special considerations and knowledge of gelatin and fill material properties and factors influencing them. Several factors affect the dissolution behavior of SGCs and subsequently affect the development of dissolution procedures. These factors include physical properties of the gelatin shell, physical and chemical properties of the fill material, chemical interaction between the gelatin shell and fill components, and moisture exchange between the shell and the fill material. In particular, moisture exchange can potentially result in brittleness of the gelatin shell, and chemical interactions between the shell and fill could result in gelatin cross-linking.

Two key considerations in the design and development of dissolution methods are the solubility of the active ingredient and solution stability of the SGCs. To establish a suitable medium, several dissolution media should be evaluated to identify the one that achieves appropriate sink conditions. Sink conditions can be defined as the volume of medium that is at least three times the saturated solubility of the API, with the lowest quantity of designated surfactant. These studies allow optimization and observing the amount of surfactant that is needed to solvate the fill material within a time that is relevant to the dissolution test. It is more reasonable that a dissolution result reflects the properties of the API under the sink conditions; however, a medium that fails to provide sink conditions may be acceptable by the USP if it is appropriately justified. Likewise, when choosing the medium, the effect of additives such as acid and salt concentration, buffer counter-ions and co-solvents, and types of enzymes and their activity must also be evaluated and justified, if used. The solubility improvement of the API depends on various factors, including the nature of the surfactant and the fill material, temperature, pH, and ionic strength. This relationship should be understood for different surfactants and compounds before executing the dissolution experiment.

Typical media for dissolution studies include: dilute hydrochloric acid (0.1 N), buffers in the physiologic pH range of 1 to 7.5 (i.e., phosphate, acetate, or citrate), simulated gastric or intestinal fluid (with or without enzymes), water, and surfactants such as Tween, Brij 35, Triton, polysorbate 80, cetyl trimethyl ammonium bromide (CTAB), sodium lauryl sulfate (SLS), and bile salts [100]. Some SGC formulations may contain a matrix or API that is not soluble in water or acidic environment and consequently, does not meet sink conditions in aqueous solution. In these instances, surfactants with a justified concentration may be added to the dissolution medium. The choice of surfactant and its concentration in relation to solubility and physical stability of the API is critical and must be optimized, understood, and justified. The addition of surfactant should reflect changes in the formulation and interactions among fill components and may shed light on the in vivo behavior of the SGCs.

Surfactants play a role in dissolution by replacing water molecules on the particle surface, which reduces interfacial tension between the solution and the surface [101]. Amidon et al. has proposed that the use of media containing surfactants is a suitable method for solubilizing such drugs because various surfactants are present in the GI fluid, e.g., bile salts, lecithin, cholesterol and its esters [102]. They consist of two distinct components, hydrophilic and hydrophobic, and are categorized into four groups according to the charge on the hydrophilic group: anionic (e.g., sodium lauryl sulfate (SLS)), cationic (e.g., cetyl trimethyl ammonium bromide (CTAB), zwitterionic (e.g., alkyl betaine) [101], and non-ionic (e.g., Tween and Triton) [103,104]. Dissolution media containing cationic surfactants are better able to discriminate dissolution rates of acidic fill materials, while anionic surfactants differentiate better for basic fill materials. SLS has been reported to be the most commonly used surfactant in dissolution studies [100]. Solubility and dissolution rate enhancement by the surfactants are a function of surfactant concentration and the size of a micelle, and its stability, all of which can be related to the critical micelle concentration (CMC) [105]. The CMC is defined as the minimum concentration of a surfactant’s monomer at which it aggregates to micelles and is characteristic for each surfactant. A lower CMC value for a given surfactant means the micelles are more stable [106]. Furthermore, the knowledge of the molecular structure of the surfactant can provide information on the size of the micelles.

It is important to note that the addition of surfactant to dissolution media can sometimes cause a decrease in the dissolution rates of some drug products, and in some instances can also distort drug peaks during high-performance liquid chromatography (HPLC) analysis ( ). In a previous study [63], it was found that an immediate-release SGC, containing a poorly soluble drug, loratadine, showed peaks distortion in the presence of SLS. A similar observation of a decrease in the dissolution of gelatin capsules with SLS at lower pH has also been reported by other research groups [107,108].

The development of simulated fluids for dissolution testing requires understanding of the physiological conditions of the GIT. It is important to note that the GIT is complex and has a regional dependence drug absorption [109]. Several physiological factors that can affect the dissolution process in vivo include: surfactants in gastric juice and bile, viscosity of the GI contents, GI mobility patterns, GI secretions, pH, buffer capacity, and co-administration of fluids or food [110]. Vertzoni et al. [111] developed a fasted-state simulated gastric fluid (FaSSGF) containing sodium taurocholate, lecithin, and pepsin at pH of 6.5 in order to assess its importance for the in vivo dissolution of lipophilic compounds. The authors concluded that simulation of the gastric content was essential in order to assess the absorption profile of lipophilic weak bases. An overview of the composition of the common in vitro bio-relevant dissolution media is provided by Klein [112] and Galia et al. [113]. Likewise, simulated dissolution media must take into account the developmental changes in gastrointestinal fluid composition because these can result in variations in luminal drug solubility between children and adults. Therefore, evaluating age-specific changes in GI fluid parameters (i.e., pepsin concentration, bile acids, luminal viscosity, pH, osmolality, etc.) is very important in order to define the composition of bio-relevant dissolution media in pediatrics [114]. Furthermore, aged population with medical conditions such as hypochlorhydria and achlorhydria have elevated gastric pH [115]. Therefore, simulated dissolution media in this population may need to be adjusted to reflect this increased pH.

The selection of dissolution apparatus is another critical step in the dissolution evaluation of SGCs, as the mixing efficiency of fill material contents with media is very much influenced by the agitation hydrodynamics, particularly to variables such as paddle rotation speed. The two commonly used methods for evaluating the dissolution properties of SGCs are the paddle and basket methods.

A basket apparatus has the advantage of enclosing SGCs. This method may be selected if SGCs are filled with a material that has a specific gravity less than that of water, where baskets prevent the SGC and its components from floating in the medium. One common problem observed using the basket is that during the dissolution experiment, the soft gel shell may disintegrate into a soft and sticky mass that can clog the basket’s mesh, generating high variability in the results. Additionally, if the fill material is hydrophobic, i.e., an oil-based fill, dispersion into fine droplets that can pass through the basket’s mesh may not take place, giving rise to a delay in dissolution that is not representative of the true properties of the SGCs. To mitigate this problem, an alternative would be using a basket with larger pores, i.e., 20 or 10 mesh sizes [116]. Pillay and Fassihi used a rotating basket method to evaluate the dissolution of lipid-based SGCs of nifedipine. Their data showed that, after six hours of dissolution test, most of the viscous oily fill formulation was still entangled within the baskets and this led to the dissolution failure [55]. This was attributed to using the standard dissolution basket with pores size of 40 mesh, combined with inappropriate hydrodynamic conditions within the basket. However, when the dissolution test was repeated using a re-designed dissolution apparatus, in this case, nifedipine SGCs showed the best dissolution profiles.

The paddle method constitutes about 70% of the dissolution methods used by FDA-approved commercial drug products [100]. This method does not use a mesh basket to contain the capsules, and so a common initial problem observed in this method is the floating of the SGCs to the surface of the dissolution medium once it breaks. In these instances, wire coils, also known as sinkers, can be used to enclose the soft gels and hold them on the bottom of the vessel [117]. This allows the fill to be better exposed to the medium (upon shell rupture) and helps to prevent the capsule from sticking to the vessel walls. The shape and size of the sinker should be selected carefully as it can impact the dissolution process, especially in cases where SGCs swell when they encounter the dissolution medium. In previous study, it was shown that the dissolution rate obtained using the paddle method was faster, highly variable at lower time points than those obtained using the basket. In contrast, the data collected using the basket dissolution apparatus showed that the method was more selective and had less variation in terms of API release profile [63]. shows examples of SGCs that are commercially available and their dissolution methods. Other research groups have evaluated the feasibility of using the USP III in evaluating the dissolution of SGCs. Monterroza and Ponce De León [118] developed a discriminating dissolution method of SGCs containing an oily suspension of micronized progesterone. They compared the dissolution profiles generated using USP 1, 2, and 3. After preliminary tests, USP 1 and USP 2 methods did not reach the target of releasing more than 85% of the API in less than 90 min. However, USP 3 showed promising prospect of releasing more than 85% of the API in less than 90 min in the presence of 250 mL of 4% of SLS in pH 6.8 phosphate.

 

In some cases, such as coated SGCs, a two-step or two-tier dissolution technique must be developed [120,121,122]. The purpose of this method is to assess the integrity of the coating in the acidic conditions of the stomach and measure the drug release in lower parts of the GIT, which have near-neutral pH conditions. Manually performing the two-step dissolution test is labor-intensive and requires well-trained analysts. For example, it requires pre-heating the second medium solution, adjusting the medium by adding the second part of the solution as well as adjusting and confirming pH for six vessels within 5 min. Typically, there are two approaches towards medium modification known as medium-addition or medium-exchange. For example, both approaches may start with an acidic step, such as 0.1 N hydrochloric acid, for a certain period, followed with a buffer step, such as phosphate buffer at pH 6.8. The specific time is chosen as needed for the individual drug product. While using either approach, the pH adjustment must be accomplished in a controlled and reproducible manner via pre-heated media. The operation of adding and adjusting the pH must be done within 5 min [123]. Zhao and co-workers described a two-step dissolution method using medium addition and paddle apparatus, in which the surfactant Tween 80 was included in the media to enhance the solubility of the API in the first stage [124]. The developed dissolution method was able to discriminate against the changes in composition, manufacturing process, and stability of the drug product. When developing a two-step dissolution procedure, several factors must be carefully examined to establish a suitable medium. The most critical step is to carefully evaluate different media to identify the one that achieves the sink conditions. The fill material may have a pH-dependent solubility, so an evaluation of the solubility of the compound in both the acidic and neutral media must be made. For instance, 0.1 N HCl and 50 mM pH 6.8 phosphate buffers are commonly used media.

The medium-addition technique, which is used for a two-step dissolution for enteric-coated capsules or two-tier dissolution testing, uses paddle or basket apparatus. This approach requires the addition of a relatively small amount of medium to each vessel in a short time. Generally, the common dissolution volumes used are in the range of 500 to 1000 mL, with 900 mL being the most commonly used in the FDA-approved drug products [100]. However, the dissolution volumes should be defined by the sink conditions. To develop a robust two-step dissolution method which can be transferred to quality control, a medium addition method is preferred where a volume of, e.g., 200 mL, can be added to 700 mL initial volume to adjust pH, and then add the surfactant, or enzyme, depending on the soft gelatin capsule drug product [124]. Furthermore, an accurate volume of the medium must be added to ensure that a volumetric error does not occur. Likewise, media addition must consider the final desired pH of the final volume. This technique is less invasive for the SGCs and is easier to conduct in a short time when running multiple batches. This approach is also less labor-intensive and allows for higher sampling throughput during the experiment run. For use in enteric-coated drug products, the API should be soluble up to the specification level in the medium of the first step to be able to detect a failure in the coating. For example, if the specification level for the first step is not more than 10% released, then this medium must be able to dissolve at least 10% of the active ingredient in the soft-gelatin capsule drug product. If the fill material is not soluble in the first-step medium, a surfactant may be added to solubilize at least 10% of the API in the fill material [124]. For use in two-tier dissolution, the fill material would require the surfactant to be present to meet solubility requirements, but also needs the enzyme to overcome the cross-linking.

For the medium-exchange approach used for enteric-coated capsules, the acid medium is drained after the first step, and a full amount of pH 6.8 buffer that has been equilibrated at similar conditions is added to the same vessel for the buffer stage. The dosage form should be undisturbed during the medium change. The complete medium replacement method resembles the medium-addition approach in that the capsules are first introduced to an acidic medium. At the end of the first step, a sample for analysis is taken, and then the dosage form is removed from the acidic conditions. Removing technique of dosage form depends on the type of dissolution apparatus. The dosage forms may be manually moved from one vessel to another. Alternatively, the entire vessel containing the acid could be removed and replaced with another vessel containing the buffer, and the dosage form is transferred to the new vessel. The quality of the SGCs dosage form is ensured by meeting the USP acceptance criteria for the acid stage, i.e., less than 10% of the API is released from the drug product during the first step of the developed dissolution technique, and therefore, the coating is considered to have passed the acid-step test. If each unit release is not less than Q + 5% for the buffer stage, then the soft gel dosage form has passed the second step of dissolution [125]. Q represents the amount of an active ingredient dissolved in the dissolution medium, expressed as a percentage of the labelled content. To overcome the challenges of manual manipulations of adding the buffer solutions and adjusting the pH during the two-step dissolution testing, other research groups have developed semi-automated dissolution systems for these measurements [125]. The media exchange technique is challenging for SGCs, especially if the capsules have softened due to the liquid exposure, soaking alone will cause some softening but may not cause the rupture of the capsule. Therefore, the transfer of the capsule or media removal without disturbing the shell may be difficult due to mechanical stress.

The European Medicines Agency (EMA) has developed its own guidance on in vitro dissolution tests for immediate-release drug products [126]. In dissolution guidance, EMA describes specifications for the quantity of active substance dissolved in a specified time, which is expressed as a percentage of API on the product label. The goal of the guidance is to set specifications to ensure batch-to-batch consistency and highlight possible problems with in vivo bioavailability. The guidance for solid immediate-release (IR) drug products from the European Pharmacopoeia (Ph. Eur. 5.17.1) has some differences compared with the FDA specifications. From a pharmaceutical perspective, the European Pharmacopoeia (Ph. Eur.) states that IR formulations should normally achieve in vitro dissolution of at least 80% of the drug substance within not more than 45 min. However, based on the USP guidance, in general, 85% or more of the drug substance should be released within 30 to 45 min.

Dissolution methods for SGCs must also consider the aspect of age-related gelatin cross-linking influencing the dissolution performance. The USP permits the use of a two-tier assessment of hard and SGCs when evidence of cross-linking is present. Evidence of cross-linking usually occurs based on visual observations during the performance of the dissolution testing. This is based on the fact that the USP general chapters on dissolution as well as disintegration and dissolution of dietary supplements , allow the addition of various enzymes based on pH of the dissolution medium when hard or SGCs and gelatin-coated tablets do not conform to the dissolution or to resolve potential cross-linking issues specifications [127]. Cross-linking evidence can come in the form of poorly dissolving gelatin shell or pellicle formation, which appears as a sac surrounding and containing the fill material after the shell is dissolved (see Section 8). To overcome cross-linking, the two-tier dissolution test would involve the addition of proteolytic enzymes such as pepsin, papain, bromelain, or pancreatin to the dissolution media and repeating the dissolution [128]. These enzymes effectively digest the peptide bonds between the amino acids making up the gelatin strands in the shell. The use of enzymes for dissolution must be done with care, as the enzymes require significant mechanical mixing to get into solution, are minimally stable in solution, and can be impacted by other components of the media, such as surfactants. If a protein denaturing surfactant [129] is used in the media, a two-step tier 2 method must be performed. The first step involves the dissolution of the capsule shell using media containing an enzyme and no surfactant as a pre-treatment step. After the capsule shell is dissolved, media containing surfactant is added to complete the dissolution and solubilization of the fill and active pharmaceutical ingredient. It was observed that using the digestive enzyme while conducting the dissolution study and afterward using the surfactant showed a better effect in the two-tier method [130].

Another important aspect that is worth discussing regarding dissolution of SGCs is the concept of an in vitro–in vivo correlation (IVIVC). This is normally used to establish a relationship between an in vivo response (e.g., amount of drug absorbed) and an in vitro physicochemical property of a dosage form. The main objective of this concept is to make sure that the in vitro properties of two or more batches of the same drug product are performing similarly under in vivo conditions. Hence, this relationship is essentially important in guiding drug development and drug approval processes that are designed to mimic the in vivo drug release. There have been various studies on IVIVC of SGCs and some have shown good correlations. Meyer et al. [53] assessed whether the changes in the in vitro dissolution of hard and soft gelatin acetaminophen capsules, as a result of gelatin cross-linking, are predictive of changes in the bioavailability of the capsules under in vivo conditions. Their data showed that the in vitro rate of dissolution of hard and SGCs decreased due to cross-linking. On the other hand, the bioequivalence studies showed that both hard and SGCs, which failed to meet the USP dissolution specification in water, but complied when tested in SGF containing pepsin, were bioequivalent to the unstressed control capsules. Based on the plasma concentration parameters, the capsules that were cross-linked to the greatest extent were not bioequivalent with the unstressed control capsules. In another study, Nishimura et al. [131] attempted to predict the human plasma drug concentrations of SGCs containing a poorly soluble drug, arundic acid. SGCs were stored at short- and long-term conditions, i.e., 15 °C for 3 months and 25 °C (60% relative humidity (RH)) for 30 months, respectively. The authors showed that the in vitro dissolution data obtained with the dissolution medium containing surfactant (i.e., 2% SLS, pH 6.8) were more effective in predicting the drug plasma concentrations following oral administrations of the SGCs under both storage conditions. Likewise, Rossi et al. [132] developed and validated a dissolution test for ritonavir SGCs based on human in vivo pharmacokinetic data. The authors used a USP II method with 900 mL of dissolution medium containing water with 0.3%, 0.5%, 0.7%, or 1% (w/v) of SLS at rotation speed of 25 rpm. Their data showed strong level A correlation between the percent of the drug dissolved versus percent absorbed. Significant in vitro–in vivo correlation was achieved using dissolution medium containing water with 0.7% SLS. In another similar study, Donato et al. [133] reported similar results on the development and validation of a dissolution test for lopinavir, a poorly water-soluble drug, in soft gel capsules, based on in vivo data. In this work, a new formulation of lopinavir was developed and its dissolution tests validated using in vivo data. All formulations were evaluated for in vitro dissolution containing 2.3% SLS at pH 6.0 and USP 1 at 25 rpm. At these conditions, the authors showed strong level A correlations for the fraction dissolved versus fraction absorbed.

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