Dissolution Performance of Empty Capsules: Does the Supplier Make a Difference?

After tablets, hard capsules are the pharmaceutical industry’s most widely used dosage delivery method. Most capsules are made of gelatin or hypromellose (hydroxypropyl methylcellulose, or HPMC), and which capsule you use depends on the formulation, the thermo-reversibility characteristics of the shell, its safety profile, and whether an adequate supply is consistently available. 

The principal ingredient in a gelatin capsule shell is—no surprise— gelatin, followed by water. It’s the same with hypromellose shells: The main ingredients are hypromellose and water. Both capsule types also include other ingredients, such as colorants and processing aids, but those account for very little of the overall composition. 

That means that the composition of the capsule shells offered by the different suppliers is very similar. Thus, when you consider dissolution performance, the question shouldn’t be “How do Supplier A’s capsules differ in dissolution from Supplier B’s?” 

Rather, you should ask “How could the dissolution performance of Supplier’s A’s capsules possibly not be equivalent to those of Supplier B?” After all, every capsule manufacturer purchases its hard-capsule-grade gelatin and its hard-capsule-grade hypromellose from the same group of third-party manufacturers. They specialize in these ingredients, and while they may tweak their products by adding a blending step or performing an additional test during quality control, they supply essentially identical gelatin and hypromellose to all the capsule manufacturers. 

The processes and machines used to make hard capsules are also virtually identical among the different manufacturers. We all still use a version of the “Colton-style” automatic capsule machine introduced in the 1930s. In addition, the processes we use to prepare the gelatin or hypromellose solutions are standard worldwide. 

That leaves the processing aids and colorants. But here again, each additive in capsules intended for pharmaceutical use is standardized and static. All have been vetted through decades of quality and regulatory approvals and documented. 

So if the functional raw materials, processing aids, colorants, and manufacturing processes and machinery are universal, why would the dissolution profile of a red capsule from Supplier A differ from a red capsule from Supplier B? They don’t. 

To demonstrate this interchangeability, samples of size 0 capsules were obtained from three different suppliers. Each one supplied a gelatin and a hypromellose capsule in quantities sufficient for testing. No specifics were given to any of the manufacturers; the request was simply for a sample of gelatin and hypromellose capsules. Next, disintegration testing was performed on all six capsules using the methodology of USP’s general chapter <701>. 

Guess what: There was no difference in disintegration among any of the gelatin capsules, nor was there any difference among the hypromellose capsules. 

In another test, a bottle of commercially available, USP-certified, 500- milligram acetaminophen gelcaps was purchased. After the gelatin coating was manually removed, the cores were manually loaded into each of the the six capsule types and dissolution testing was performed on 36 capsules (six capsules of each capsule type and supplier) as specified in USP <711>. All the capsules met the dissolution testing criteria. 

To further demonstrate the interchangeability of the capsule shells, the data was examined statistically. Again, no difference was found in the dissolution results among the three gelatin capsules, and none was found among the three hypromellose capsules. There was, however, a statistical difference between the performance of the gelatin capsules and that of hypromellose capsules. That was expected because they’re made from different materials. 

But when the materials are the same, dissolution performance is, too. It’s thus puzzling that the pharmaceutical industry continues to spend time and money—day after day, year after year—demonstrating again and again that two capsules that cannot possibly be different are indeed equivalent. 

Are the capsules identical? No. But gelatin capsule shells from the major manufacturers act similarly because the amount of true variability between the shell composition, starting materials, and manufacturing process is extremely small. These excipients— which is what empty gelatin capsules are—should be treated as interchangeable when made by the major capsule suppliers while still adhering to the current rules governing reportable changes. Hypromellose capsules, although not statistically equivalent in performance to the gelatin capsules tested, performed interchangeably regardless of the manufacturer. So they, too, should be treated as interchangeable while still adhering to the annual reporting rules applicable to excipients.