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D 34 May 2017 Tablets & Capsules dissolution testing Dissolution of oil-filled softgels: Formulation and analytical development Claudia Silva, Jose Acosta, and Diego Monterroza Procaps Quality by Design (QbD) has proven to be a cost-effective approach for developing and manufacturing pharmaceuticals. This article describes how the authors selected the gelatin and plasticizer used in the shell of an oil-filled softgel formulation. It also presents a case study in which a Design of Experiments (DoE) approach is used to establish a dissolution test suitable for the softgel product. issolution performance is one of the most frequent issues encountered during product development of soft- gels. The difficulty stems in part from the terminal reac- tive amino or carboxyl groups of the gelatin, which tend to crosslink and can form insoluble high-molecular- weight chains that limit the release of the fill material into the dissolution media. The crosslinking potential depends on the content of the high-molecular-weight chains, the types of free groups that react in gelatin, and the reactive impurities in the fill material's excipients. In addition, a number of gelatin properties—including gelatin type and molecular weight—and the plasticizers used determine dissolution performance. Gelatin type. Because of basic or acidic hydrolysis, gelatin's amino acid composition breaks down into its constituent forms, glutamine and asparagine in type A gelatin, and glutamic and aspartic acid in type B [1]. These differences determine the isoelectric point (the pH at which a molecule carries no net electrical charge) for each gelatin type— basic pH of 8 to 9 for type A and acidic pH of 4.8 to 5.5 for type B. This, in turn, defines the gelatin's compatibility with basic or acidic APIs. It has also been reported that at the gelatin's isoelectric point, swelling is at its minimum and gel strength is at its maxi- mum. These are important facts to consider when formu- lating gelatin for capsules and for evaluating dissolution performance, because in most dissolution media (buffered solutions) both gelatin types will be in their acidic form [1]. Molecular weight. Commercial gelatins are highly heterogeneous in their molecular weight distribution because they are commonly obtained by mixing fractions of different blooms. In addition, the higher the molecular weight, the greater the crosslinking potential. This rela- tionship is based on the amount of macrogel molecules in the gelatin. Plasticizers. Plasticizers act as mechanical stabilizers by increasing the capsule shell's elasticity and reducing stress related to shrinkage during the encapsulation and drying processes. Formulators select the type and use level of the plasticizer based on the product's features (fill material, size, shape, and end use) and storage condi- tions. Most common plasticizers used in softgel formula- tions are polyalcohols or their mixtures that act as direct or indirect plasticizers, either interacting to form the gelatin network or serving as moisturizing agents. In either case, the interaction among the fill material, shell, and environment will differ, as will disintegration and dis- solution performance, hardness, mechanical resistance, and clumping tendency [2]. As with the type and content of plasticizer, the ratio (by dry weight) of plasticizer-to-gelatin is related to the mechanical properties and therefore the physical stability of the shell. This should be taken into account according to the capsule's size and the product's intended use [2]. If