3.1. Solvent Casting

At present, solvent casting has emerged as the widely preferred technique for practical, feasible manufacturing and the scaling up of oral films [100]. On a small scale, for the preparation of ODFs in a laboratory setting, polymer(s) and other necessary ingredients are dissolved in a suitable solvent to form a homogeneous solution. The solution is then cast onto a substrate, and the solvent is allowed to evaporate, leaving behind a thin film. The manufacturing process of ODFs on an industrial scale using the solvent casting technique consists of multiple steps, starting with the precise dispensing of the drug, excipients, and non-toxic FDA-approved class III solvents, followed by their homogeneous dispersion in a low-shear or high-shear mixer under thermostatic control [4]. Nonetheless, it is not recommended to utilize high-shear mixers when dealing with encapsulated drug actives, as this method can lead to the removal of the encapsulating material. The slurry undergoes solvent evaporation within a hot-air oven set at a designated temperature. Subsequently, it is applied onto a meticulously chosen liner using a knife-over-roll coater equipped with a precise pin gauge. The resulting dried laminates are rolled up into master rolls and subsequently cut into individual dose units based on the desired dimensions of the ODF. These single-dose units are enclosed within pouches or sachets using packaging and sealing machinery. The solvent casting method used to prepare ODFs is similar to the manufacturing process of buccal film, as depicted in Figure 1. The child-resistant and tamper-proof packaging material is designed to protect against adverse environmental conditions and ensure ease of use. It is of utmost importance to determine the weight of each film unit being packaged, as the drug dosage in the ODF is directly dependent on its weight. One of the key advantages of this dosage form is its flexibility in generating multiple dose units simply by adjusting the size of the film. Various factors, such as the solvent evaporation rate, airflow velocity of the hot air, pin gauge dimensions, and conveyor belt speed, influence the formation of the cast film. Scaling up the production of ODFs using the solvent casting technique poses several challenges. Equipment adaptation is often necessary, and the transition to larger-scale equipment must preserve the desired film characteristics. Maintaining uniformity and homogeneity of the film on a larger scale is crucial, as variabilities in the mixing and casting processes can lead to inconsistencies. Ensuring the integrity of the film, and avoiding defects such as cracking or uneven thickness is a challenge that grows with the scale of production. Implementing effective quality control measures becomes more intricate, demanding rigorous batch-to-batch consistency and adherence to regulatory standards. The increased scale also introduces considerations of elevated costs related to equipment, materials, and energy consumption. Environmental factors like temperature and humidity become more pronounced in larger-scale production, affecting the drying process and the overall quality of the films. Addressing these challenges requires meticulous planning, optimization of processes, and a commitment to maintaining high-quality standards throughout the scaled-up production of ODFs.

Schematic diagram displaying the typical solvent casting processes involved in orodispersible film manufacture (adapted from [4], published by MDPI, 2021).

Quetiapine fumarate ODF production, at a pilot scale, has been executed through the solvent casting method, following the principles of quality by design [101]. The optimized films were prepared by employing HPMC E5 as the film former and propylene glycol as the plasticizer at a temperature range of 65–70 °C.

The viscoelastic characteristics of the casting solution or dispersion significantly influence the film’s characteristics, such as content uniformity, thickness, morphology, and drug release. To overcome the typical problem of poor drug loading, investigators have developed a porous ODF using HPMC polymer via the solvent casting method [10]. A proposed solution for addressing the issue of content uniformity is the introduction of a new unit-dose plate that can be filled with the required volume of a constituent mixture [102]. An alternative method to ensure the content’s uniformity is by using doctor-blade film coaters, wherein a slurry is uniformly applied to a substrate through a metering blade to achieve the desired thickness [100]. To ensure the uniformity of the dispersion, the rheological properties and solids’ content are estimated, and in-process sterility testing is conducted to identify any potential bioburden. Various researchers have observed that the mechanical properties of the films, such as folding endurance, tensile strength, toughness, puncture strength, and film thickness, were significantly impacted by the formulation compositions [70,75]. For instance, different domperidone ODFs prepared using PVPK-90 were discovered to significantly influence the physical properties, mechanical properties, film thickness, and drug release rate of the resulting films [103]. The formation of the cast film on the selected liner is influenced by several variables, which encompass the rate of solvent evaporation, air flow velocity, positioning of the heat source, pin gauge dimensions, and conveyor belt speed [104]. The characteristics of the intermediate liner, such as the contact angles and surface tensions, can influence the film’s quality. Investigations conducted on hydrochlorothiazide ODFs prepared with HPC or HPMC as film-forming agents have demonstrated remarkable influences of the production process on the film’s attributes [105]. The film can be manufactured similarly as a transdermal patch—as a large sheet that can be cut into specific dimensions consisting of individual dosage units and packaged in pharmaceutically acceptable packaging materials. Such a formulation advancement would enable users to readily recognize their medication, thereby enhancing safety and adherence. Lately, researchers have demonstrated that the inclusion of nanocrystal dispersions or microparticles in ODFs can lead to improved drug dissolution rates [106] or enable extended drug delivery [107]. Nevertheless, it is important to consider that the inclusion of such particles may potentially impact the mechanical characteristics of the film.