**1. Introduction**

Gastro-resistant formulations are an example of the most common type of modified drug release systems. Gastro-resistant forms of drug administration allow to:


Gastro-resistant soft gelatin capsules can prove their usefulness in oral administration of drugs of irritating or acid-labile nature, often displaying at the same time enhanced bioavailability in a liquid form, which can be considered an advantage to coated tablets [2]. The most obvious examples of the substances that need to be formulated in gastro-resistant dosage forms are non-steroidal anti-inflammatory drugs (NSAIDs), which are irritating to gastric mucosa.

The products in the form of gastro-resistant capsules usually are designed as conventional hard capsule shells filled with the enteric-coated pellets or minitablets. Manufacturing of gastro-resistant soft capsules, however, is a challenge. Due to the liquid fill, modification of the drug release rate from soft capsules can be achieved only by modification of the capsule shell to make it resistant to acidic pH. This issue can be approached by-coating of standard capsules with acid-resistant polymers such as methacrylic acid—methyl acrylate copolymers (e.g., Eudragit L or S ®) [3]. A less popular alternative

is incorporation of gastro-resistant polymers in the shell material used to form the capsules [4]. Both approaches are technologically perplexing at some points, although modification of the shell material can be considered more beneficial from both economic and technological point of view. However, it is not ye<sup>t</sup> utilized in commercial products. It is substantial to take into consideration that any changes in the composition of the film-forming mixture can result in significant alteration of the overall physicochemical properties of the prepared films, that can lead to the loss of their potential to be formed into capsules in a conventional manufacturing process.

A very important issue associated with the development of a new capsule shell composition is to identify the physiochemical phenomena that can be utilized in designing and manufacturing of modified release gelatin-based films. In our previous work, selection of the most e ffective modification of the shell material composition was performed, and their microstructure and barrier properties were described [5,6]. However, there are still a few unexplained issues in the description of the phenomena that lead to formation of the films, as well as the changes that the films undergo when exposed to various conditions. Therefore, in the present work, a more detailed investigation of the events associated with the formation of the gastro-resistant film was performed and further, the structural changes upon submersion of such films in acidic dissolution fluid is performed. For the purpose of better characterization of the films and film formation processes, several modern techniques may be employed. In the present research, a scanning electron microscopy (SEM), confocal laser scanning microscopy (CLSM), confocal Raman microscopy and quartz crystal microbalance with dissipation monitoring (QCM-D) were used. Additionally, the barrier properties of the films against oxygen were evaluated.

In comparison to tablets or hard capsules, the transfer of a new technology for soft capsules from the lab to the production site is much more complicated, and a scale-up procedure may be complicated and time-consuming. One of the main issues when soft capsules are developed is a poor access to a lab-scale equipment that could allow to assess the utility of the modified films for capsule formation. The most problematic is the fact that, at a commercial scale, specific rheological and mechanical properties of the film-forming material are required [7–9]. The fact that the shell-forming material has to be tested on a large scale, significantly increases the cost of technology development. In our present work, the lab-scale production process of the soft capsules is presented, utilizing a simple mold for suppositories, what allowed to evaluate the shell compatibility with the filling material.

#### **2. Materials and Methods**
