Many of the early papers that addressed capsules made from hydroxypropyl methylcellulose (HPMC), or hypromellose, stated that they didn’t lose their mechanical properties with a reduction in moisture content1-3. (Gelatin capsules become brittle when their moisture content—typically 13 to 16 percent—falls below 10 percent.)
In 1998, researchers at Shionogi Qualicaps published the results of the first study that described the use of HPMC capsules. They concluded that an HPMC capsule “maintains mechanical integrity under extremely low moisture conditions, such as created by the addition of excipients that absorb water”1. Jones first described the ability of HPMC capsules to retain their integrity when filled with “materials that are sufficiently hygroscopic to remove enough moisture from gelatin capsules to cause them to break and split”3.
The literature since that time includes many references to HPMC capsules being useful when filling capsules with hygroscopic formulations. It is possible, however, to interpret that statement about usefulness in two ways. It could mean that the capsules retain their integrity when filled with hygroscopic formulations and exposed to varying conditions. Or it could mean that HPMC capsules filled with hygroscopic substances retain their properties when placed in pharmaceutical packaging as per the standard procedures for stability testing.
Two studies that applied the first interpretation in setting up their protocols were published in 2015. In the first, Al-Tabakha et al. carried out a hygroscopicity and stress test by filling capsules with polyvinylpyrrolidone (PVP), a hygroscopic excipient, and exposing them to a range of relative humidity (RH) levels4. The researchers compared one type of gelatin capsule and two types of HPMC capsules. At the highest RH, the PVP in the gelatin capsules liquefied and leaked. The HPMC capsules had a slower rate of uptake than the gelatin capsules, and none of the capsule types protected their contents from moisture. Based on their findings, the authors questioned the claim that HPMC capsules are suitable for hygroscopic formulations.
The second study, by Braham et al., included a similar series of tests5. The researchers compared gelatin capsules with HPMC capsules produced by the hot-mold process. They filled samples of both capsule types with spray-dried lactose and compared the moisture uptake of empty and filled capsules. The gelatin capsules showed a stronger attraction for moisture than the HPMC capsules and had a different mechanism of water absorption. The lactose in both types of capsule showed signs of crystallization as the RH increased from 50 to 70 percent. The authors concluded that the moisture properties of the capsules were different and, based upon the changes in the lactose form, neither capsule type adequately protected its contents.
Both studies were perfectly correct in their conclusions, but in applying a literal rather than a qualified interpretation, they misunderstood the claims of the capsule manufacturers, i.e., that HPMC capsules provide a degree of protection from hygroscopic materials when the filled capsules are packaged in sealed containers (blisters or bottles) and are not exposed to the ranges of RH used in the two studies. Pharmaceutical manufacturers can use desiccants in the packaging to maintain a low RH, if required, with no risk of making the shells brittle, as would happen with gelatin capsules. The hygroscopic fills would embrittle the gelatin worse than the HPMC even when stored properly. Pradaxa is a good example of a filled HPMC capsule that was chosen for its low moisture content to protect the API6.
References
1. Ogura T, Furuya Y, and Matsuura S, Pharm. HPMC capsules an alternative to gelatin. Tech Europe, Nov 1998, article No. 0310, 5.
2. Nagata S. Advantages to HPMC capsules; A new generation’s hard capsules. Drug Deliv Technol, 2002, 2(2), 1-5.
3. Jones, BE. A new solution for formulation challenges. Business Briefings, Pharma Outsourcing, Jan 2004, 56-61.
4. Al-Tabakha MM, Arida AI, Fahelelbom KMS, Sadek B, and Saeed DA. Influence of shell composition on the performance indicators of hypromellose capsules in comparison to hard gelatin capsules. Drug Dev Ind Pharm, 2015, early online, 1-12. 5. Braham AS, Tewes F, and Healy AM. Moisture diffusion and permeability characteristics of hydroxypropylmethylcellulose and hard gelatin capsules. Int J Pharm, 2015, 478, 796-803.
6. European Medicines Agency. Pradaxa product information. http:// bit.ly/TCPradaxa. Accessed November 11, 2016.
Brian E. Jones is a consultant on hard capsules and a scientific advisor to Qualicaps, Whitsett, NC. He is a senior honorary lecturer at the Welsh School of Pharmacy, Cardiff University, UK. E-mail: bjcapsules@ntlworld.com. Jones is co-editor of “Pharmaceutical Capsules,” now in its second edition