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Tablets & Capsules April 2019 37 eye on Xavier Parissaux and Olaf Haeusler Roquette excipients This edition of Eye on Excipients com- pares the performance and stability characteristics of glycerin and sorbi- tol-sorbitan solution when used as plas- ticizers for softgel capsule formulation. Soft gelatin capsules (softgels) are an important dosage form option for p h a r m a c e u t i c a l m a n u f a c t u r e r s because many patients prefer them over other solid oral dosage forms and perceive them as easy to swal- low, which leads to improved patient compliance [1]. Softgels can also allow formulators to increase the absorption rate of the active pharma- ceutical ingredient (API) by altering the fill formulation (from lipophilic to hydrophilic, for example), help ensure dose uniformity with low- d o s e d r u g p r o d u c t s , a n d h e l p improve drug stability. However, softgels require formula- tors to carefully select the right com- bination of shell ingredients and liquid-fill composition to ensure dos- age integrity. A key shell ingredient that greatly influences how the shell and liquid fill interact is the plasti- cizer. A plasticizer is a substance added to the capsule shell's gelatin base to improve its elasticity and durability. Selecting the best plasticizer mini- mizes the risk of defects such as stick- ing, brittleness, and leaking and can even improve productivity. Histori- cally, softgel manufacturers have used glycerin as a plasticizer, but glycerin presents two major challenges when used in softgel capsule formulation. First, glycerin is hygroscopic. While water is the one of the most effective plasticizers, it is also very mobile and volatile. A hygroscopic plasticizer cannot ensure constant and long-term plasticization in a softgel formulation unless the capsules are kept in tightly controlled temperature and humidity conditions. This is because the water content is able to migrate between the capsule shell and the liquid fill and/or between the shell and the surrounding environment, as shown in Figure 1. Second, glycerin has the capacity to migrate out of the gelatin network in the capsule shell and into the liq- uid fill (Figure 1), causing a progres- sive hardening of the shell. Indeed, softgels with a hydrophilic fill (based on low-molecular-weight PEG) or a self-emulsifying system can lose mechanical integrity after just several months of storage, resulting in leaks and performance loss. Both of these challenges are common with formu- lations that use glycerin. One way to prevent such migra- tion phenomena is to use a plasticizer made from an aqueous solution of sorbitol and sorbitan. Sorbitol is a sugar alcohol derived from glucose, and sorbitan (Figure 2) is obtained by partially dehydrating liquid sorbitol. A sorbitol-sorbitan solution (such as Roquette's Polysorb 85/70/00) pro- vides the same plasticizing benefits as glycerin but without significant m i g r a t i o n p h e n o m e n a a n d t h e related loss in plasticity. Also, due to its complex composition, sorbi- tol-sorbitan solution is anti-crystal- lized, which helps prevent the sorbi- tol from crystallizing at the capsule surface during storage, causing unde- sirable shell cloudiness. Figure 3 compares the hardness over time for softgels plasticized with glycerin versus softgels plasticized with sorbitol-sorbitan solution (Poly- sorb 85/70/00). The softgel formula- tions contained PEG 400 as a filler and were evaluated for their elasticity over a 6-month period, with the only difference between the two samples Figure 1 Typical migration processes in softgels with hydrophilic fill and water exchange Plasticizer Water Water Figure 2 Molecular structure of 1,4-sorbitan HO OH OH OH O