Issue link: https://www.e-digitaleditions.com/i/626800
64 January 2016 Tablets & Capsules After tablets, hard capsules are the pharmaceutical industry's most widely used dosage delivery method. Most capsules are made of gelatin or hypromellose (hydroxypropyl methyl- cellulose, or HPMC), and which cap- sule you use depends on the formula- tion, the thermo-reversibility characteristics of the shell, its safety profile, and whether an adequate sup- ply 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 col- orants 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 differ- ent suppliers is very similar. Thus, when you consider dissolution perfor- mance, 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 disso- lution performance of Supplier's A's capsules possibly not be equivalent to those of Supplier B?" After all, every capsule manufac- turer purchases its hard-capsule-grade gelatin and its hard-capsule-grade hypromellose from the same group of third-party manufacturers. They spe- cialize in these ingredients, and while they may tweak their products by adding a blending step or performing an additional test during quality con- trol, 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 manufac- turers. We all still use a version of the "Colton-style" automatic capsule machine introduced in the 1930s. In addition, the processes we use to pre- pare the gelatin or hypromellose solu- tions are standard worldwide. That leaves the processing aids and colorants. But here again, each addi- tive in capsules intended for pharma- ceutical 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 manu- facturing 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 interchange- ability, samples of size 0 capsules were obtained from three different suppli- ers. Each one supplied a gelatin and a hypromellose capsule in quantities suf- ficient 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 per- formed on all six capsules using the methodology of USP's general chapter <701>. Guess what: There was no differ- ence in disintegration among any of the gelatin capsules, nor was there any difference among the hypromellose capsules. In another test, a bottle of commer- cially 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 test- ing was performed on 36 capsules (six capsules of each capsule type and sup- plier) as specified in USP <711>. All the capsules met the dissolution test- ing criteria. To further demonstrate the inter- changeability of the capsule shells, the data was examined statistically. Again, no difference was found in the dissolu- tion results among the three gelatin capsules, and none was found among the three hypromellose capsules. There was, however, a statistical differ- ence between the performance of the gelatin capsules and that of hypromel- lose 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 pharmaceuti- cal 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 interchange- able when made by the major capsule suppliers while still adhering to the current rules governing reportable changes. Hypromellose capsules, although not statistically equivalent in perfor- mance 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 excipi- ents. T&C Christopher Kotevich is technical director at Suhe- ung North America, 428 East Saturn Street, Brea, CA 92821. Tel. 714 854 9887. Website: www.suheung.com b a c k p a g e Dissolution performance of empty capsules: Does the supplier make a difference?