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Hard capsules have traditionally been used to deliver powder or gran- ule formulations, but in recent years, formulators have increasingly used them to deliver oily liquids and semi- solid formulations. These lipid-based f o r m u l a t i o n s ( L B F s ) t y p i c a l l y improve the solubility, dissolution, and absorption of poorly soluble APIs. For example, systems compris- ing mixtures of surfactant and oil, or self-emulsifying drug delivery sys- tems (SEDDS), result in a dispersion of fine emulsion droplets in situ [1]. Softgel capsules have been widely used for LBFs, but liquid-filled hard capsules (LFHCs) provide an attrac- tive alternative. LFHCs are typically composed of a shell of gelatin, a blend of gelatin and polyethylene glycol (PEG), or hydroxypropyl methylcellulose (HPMC). Unlike softgels, hard capsules don't contain plasticizers, reducing the potential for API migration from the fill to the capsule shell. Also, assuming proper engineering controls are in place to protect the operator, hard capsules can be filled at higher temperatures than softgels—up to 50°C for gelatin and 70°C for HPMC. When formulating a LFHC, you must ensure that the fill material is compatible with the capsule shell to maintain the formulation's physical and chemical stability. A key factor is the ex tent of water exchange between the formulation and the capsule, which can lead to unac- ceptable changes in the capsule's mechanical behavior. Understand- ing how the presence of water or hydrophilic components in a formu- lation may affect the capsule shell can guide formulators and help to minimize the time and costs associ- ated with compatibility tests [2]. Because gelatin capsules contain 13 to 16 percent moisture, hygro- scopic excipients such as glycerin, propylene glycol, and liquid PEGs cannot be used on their own as they will cause the gelatin capsule shell to become brittle and fracture. HPMC capsules contain less moisture and can be a good option for hygro- scopic excipients. However, PEG 400 and 600 can cause PEG diffusion in HPMC capsules, resulting in dis- tortion and swelling of the capsule wall. PEG excipients with a molecu- lar weight of 900 or greater do not cause this problem [3]. Several com- patibility studies have evaluated the effect of many popular liquid and semi-solid excipients on hard gelatin, HPMC, and PEG-gelatin capsules containing up to 5 percent PEG [4]. Most LFHC filling systems are optimized for nominal fill-solution viscosities between 100 and 1,000 centipoise. Unlike traditional pow- der- or pellet-filled capsules, LFHCs require band sealing to ensure prod- uct integrity. Sealing systems either chemically bond the capsule's cap and body or apply an external band-sealing solution. The band- sealing solution should match the composition of the capsule, and solu- tions are available in various colors to provide additional product differenti- ation and branding options. Because LFHCs can be accurately filled using manual or semi-manual filling methods, they are a viable alternative for early formulation eval- uation and human or animal studies. External band seals may be applied by hand or using table-top, R&D- scale equipment, providing a quick and efficient way to evaluate new prototypes. This speeds up the initia- tion of human clinical studies and helps companies match manufactur- ing output to clinical demand. Scale-up is very linear, allowing manufacturers to scale the process train in proportion to demand with- out the need for dedicated drying equipment and prolonged curing time, as with many softgel formula- tions. Commercial capsule fillers often use extremely accurate volu- metric pumps to ensure dose unifor- mity. Automated filling and band s e a l i n g e q u i p m e n t c a n r e a d i l y achieve commercial production capacities while maintaining opera- tional efficiencies typically associated with traditional capsule-filling. T&C References 1. A. Machado et al. "A micro- structural study of water effects in lipid-based pharmaceutical formula- tions for liquid filling of capsules." European Journal of Pharmaceutical Sci- ences. Vol. 90, pages 64-75. 2. A. Machado et al. "Understand- ing capsule compatibility with lip- id-based formulations: Assessment of mechanical properties of gelatin and HPMC capsules after equilibration with formulations." Poster W4062, presented at AAPS 2015. 3. G. Rowley. "Filling of liquids and semi-solids into hard two-piece capsules." Pharmaceutical Capsules, 2 nd edition. Edited by F. Podczeck and B. Jones. Pharmaceutical Press. 2004. pages 169-194. 4. A. Yamashita et al. Japan Journal of Pharmaceutical Health Care Science. Vol. 27, No. 6. 2001. pages 576-582. Gabriela Dujovny is scientific business development manager and Ryan Taro is director of scientific business development at Qualicaps (336 4 4 9 3 9 0 0 , w w w . qualicaps.com). b a c k p a g e Liquid capsule filling for poorly soluble drugs