Capsules: How to Assess and Prevent Brittleness of Hard Gelatin Capsules

Capsules have come a long way since they were patented in 1834. Today they are one of the most common and popular means of orally administering pharmaceuticals and dietary supplements. Valued at $1.5 billion in 2016, the global market for empty gelatin capsule shells is forecast to increase to $2.21 billion in 2021, a compound annual growth rate of 7.2 percent¹.

As Figure 1 shows, in 2007 only 6 percent of approved drug products containing a new chemical entity used a capsule, but in 2015, the percentage tripled. This is because capsules are faster and simpler to formulate than tablets and other dosage forms and can thus reach the market more quickly. 

Since they were first manufactured on a large scale in the USA in 1870, most hard capsules are made from gelatin, which has numerous desirable properties². Other properties of gelatin capsules, however, can pose a challenge during product development. The capsules can become brittle, for example, when stored at low relative humidity (RH), when filled with formulations containing hygroscopic substances, or when exposed to a desiccant. Generally, the brittleness of empty capsules becomes an issue when RH falls below 40 percent. See Figure 2³. 

This article discusses factors that influence brittleness and how to mitigate their effect so you can develop more robust capsules and capsule formulations. 

Brittleness 

Before studying capsule brittleness, we must define it. Brittleness of a material refers to the property of breaking without much permanent distortion. It is the opposite of elasticity, which describes a solid’s ability to be stretched/deformed and then return to its original size⁴. Both phenomena can be observed when a solid—or in the case of gelatin, a polymer—is subjected to some force (energy). If the material is elastic, it accommodates the force through deformation, molecular movements (vibration, rotation, and small translations), and heat. Brittle materials don’t allow such modes of movements, and the impact energy is confined within a small localized area sufficient to directly rupture the material’s bonds. 

Adding plasticizers—a common means of reducing the stiffness of polymers—works because it decreases the cohesive intermolecular forces along the polymer chain [5]. In hard gelatin capsules, water acts as the plasticizer. Therefore, a loss of moisture, perhaps due to low RH, causes the gelatin capsules to become brittle. 

Assessing the Gelatin Polymer 

Hard shell capsules are manufactured from a stock solution of gelatin that also contains colorants and various process additives. To form capsules, stainless steel mold pins are dipped into the solution, coating them in film. After the film dries, the capsules are removed from the molds and cut to length. Next, the caps and bodies are assembled, and the complete capsules are sorted, printed, and packaged. 

The gelatin polymer is derived from the chemical degradation of collagen, and how it behaves depends on whether its macromolecules form a collagen-like helix or a coil configuration. In helical form, the gelatin is suitable for use at ordinary temperatures. In the coil form, which is more amorphous, the gelatin is a typical rigid-chain polymer and behaves as a brittle—and thus impractical—material due to the absence of water⁶. 

Not all gelatin types perform the same way, and you can learn about a gelatin’s performance in terms of brittleness by analyzing two parameters: glass transition temperature and polymer crystallinity. 

Glass Transition Temperature

Abbreviated Tg, the glass transition temperature is the temperature at which the mechanical properties of a polymer change from those of an elastic material to those of a brittle one due to changes in chain mobility⁷. 

Polymer crystallinity. Gelatin coexists in two states: a crystalline, molecular aggregate state that follows a defined pattern and an amorphous state with no defined shape. As with other polymers, the crystalline form of gelatin is brittle.

 Differential scanning calorimetry (DSC) is helpful in assessing gelatin performance. DSC is a thermoanalytical technique in which the difference in the amount of heat required to increase the temperature of a sample and a reference are measured as a function of temperature. The principle underlying this technique is that when the sample undergoes a physical transformation, such as phase transitions, more or less heat will need to flow to it than to the reference in order to maintain both at the same temperature. Figure 4 shows a DSC diagram for gelatin.

Note three singularities: 

1. The Tg at which the sample undergoes a change in heat capacity 
2. Crystallization (melt temperature 1 in the figure), the point at which the molecules obtain freedom of motion and spontaneously arrange themselves into a crystalline form. This peak can be used to confirm that crystallization occurs in the sample, and the area under curve gives information about the quantity of this phase. 
3. The melting point (melt temperature 2) at which the polymer chains can move freely. 

We conducted an in-house study using two gelatin samples—Gelatin 6 and Gelatin 15—that had different degrees of brittleness. Capsules made from each were analyzed for their thermal properties using DSC. Figure 5 shows the results. 

As Table 1 shows, Gelatin 15 has a slightly lower Tg but is less homogenous, and its crystallinity is three times higher than that of Gelatin 6. Therefore, we concluded that the mechanical properties of Gelatin 6 are superior to those of Gelatin 15. 

The Effect of Pigments 

Pigments provide opacity and create a protective barrier to harmful radiation, typically from the sun or other light sources. Titanium dioxide (TiO2)—the most common pigment in capsules—has a refractive index of 2.27 to 2.71, which differs markedly from that of gelatin (1.24). This difference helps protect the gelatin because when a ray of light passes from a substance of low refractive index to a substance of high refractive index, a structure with a high radiation barrier is formed^{8, 9}. 

Pigments also have a significant impact on mechanical properties: The higher the pigment content, the greater the brittleness. Therefore, it’s critical to formulate the capsules using the optimal amount of pigment. 

The UV-Vis spectra for gelatin capsules shown in Figure 6 indicate that when the TiO 2 concentration is around 3 percent, light transmission is very low. They also show that adding pigment in excess of that amount doesn’t protect the capsules or their contents any better. In fact, the performance of the gelatin capsules decreases in terms of brittleness, so avoid using more of this additive than is necessary. 

Manufacturing Conditions 

It’s well known that molecular weight and molecular weight distribution can markedly affect the mechanical properties of a polymer. Therefore, seek a polymer of optimal molecular weight: high enough to provide good mechanical properties but not so high that it degrades processability. 

It’s also known that subjecting gelatin to excessive heat for too long can cause the polymer chains to fragment, which reduces their molecular weight and diminishes capsule performance due to brittleness. Therefore, in processes that require the gelatin to be heated, keep the heating period as short as possible. When making capsules, the gelatin is usually dissolved in 70º to 80ºC demineralized water in jacketed stainless steel tanks. That process typically lasts about 1 hour. 

Quality Control 

Reputable manufacturers have a set of procedures to ensure that capsules are of high quality when they reach consumers. The capsules should not have cracks, break when extracted from the package, or—even worse—rupture and allow the ingredients to spill out. 

To ensure your products won’t suffer from those problems, assess the strength of the capsules to determine whether they can withstand the forces to which they will be subjected. Compression and tension tests offer a technical approach with quantifiable results. However, be sure to vary the force applied when you conduct your analysis. Don’t just subject the capsules to the same amount of force the entire time. 

Figure 7 shows two approaches to force testing. The results in Figure 7a represent the force applied to a capsule extracted from a blister, while Figure 7b represents the force applied if the capsules crashed into one another in a container. For quality control, use the force profile that best represents the conditions that the capsules must endure. 

Another way to nondestructively assess the mechanical properties of capsules is to measure their refractive index. As discussed above, the index correlates to how radiation passes through a medium, and any changes in it can be correlated to changes in the mechanical properties of the gelatin capsules. The results shown in Figure 8 illustrate how the refractive index relates to a capsule’s resistance to breakage, which decreases as the RH of the storage environment decreases. 

Conclusion 

Extensive experience in the field of capsule manufacturing is needed to identify the fundamental properties that affect capsule performance. Therefore, seek manufacturers who have that experience. At the same time, recognize that the manufacturing process and storage conditions are not the only factors that can cause brittleness. 

References 

1. Empty capsules market by product: Global forecast to 2021. Report by Markets and Markets, May 2016. Online: http://bit.ly/ShellTC117. Accessed December 12, 2016. 

2. M.E. Aulton (Ed.) Pharmaceutics: The science of dosage form design. 2002. Churchill Livingstone, Philadelphia. 

3. Kontny M.J. et al. Gelatin capsule brittleness as a function of relative humidity at room temperature. Int J Pharm 54(1) 1989, 79-85.

4. Unit 8, chapter 27: The physical properties of matter. CPO Science Foundations of Physics. Online: http://bit.ly/PhysPropTC. Accessed December 12, 2016. 

5. Bhargava A.K. and Sharma C.P. (Eds.) Mechanical behaviour and testing of materials. 2011. PHI Learning, Delhi. 

6. Lesson 14 course notes: Mechanical properties of materials. University of Texas-Arlington. Online: http://bit.ly/MechPropTC. Accessed December 12, 2016. 

7. Kozlov P.V. et al. The structure and properties of solid gelatin and the principles of their modification. Polymer 24(6) 1983, 651-666. 

8. Diez F. Hard capsules protect drugs from radiation. EPM, blog post, October 2015. http://bit.ly/DiezEPM. Accessed December 12, 2016. 

9. Son, Y. et al. Refractive index as a surrogate nondestructive measure of capsule brittleness. Respiratory Drug Delivery, vol. 2, 2014, 493-496.