Orally Disintegrating Tablets: The Effect of Recent FDA Guidance on ODT Technologies and Applications - Pharmaceutical Technology

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Orally Disintegrating Tablets: The Effect of Recent FDA Guidance on ODT Technologies and Applications
The authors describe the various available technologies used in orally disintegrating tablets.

Pharmaceutical Technology

Table III: Comparison of product characteristics of various technologies for orally disintegrating tablets.
The ability of a particular ODT technology to meet the desirable ODT quality and performance attributes, including the recommendations of the FDA guidance document, largely depends upon the formulation and process approach on which the ODT is based. A brief overview of each technology platform is further discussed in this article, and a comparison of product process requirements and attributes is provided in Table III. Examples of specific product performance are also given in Table IV.

Lyophilized products

Table IV: Disintegration times for orally disintegrating tablets (6).
Zydis. The Zydis technology is an example of a technology platform for lyophilized ODT products. The basic formulation and process for lyophilized ODTs are all similar, but there are some important differences between each lyphilized ODT technology, which result in significant variation in performance.

To create ODTs using the Zydis lyophilization technology, the active pharmaceutical ingredient (API) is dispersed in a matrix consisting of a polymeric structure former (e.g., gelatin) and a saccharide (typically mannitol) dissolved in water. In the finished product, the glassy amorphous structure of the polymeric component imparts strength and resilience while retaining some flexibility. The specific grade of gelatin typically used and its associated dissolution characteristics ensure a smooth, rapid melt in the mouth. Mannitol crystallizes during freezing, thereby providing an elegant appearance and rigidity and ensuring that the product is robust to handling and transport. Because mannitol is readily soluble, it also has the function of improving texture, taste, and mouthfeel.

Depending on its solubility, the API may be dissolved in the matrix or dispersed to form a homogenous suspension for dosing. The liquid dosing process ensures good dose uniformity and can accommodate extremely low-dose strengths (i.e., micrograms), particularly important for low-dose pediatric applications.

For suspension products, dose strengths of up to 400 mg can be accommodated, and the API is typically micronized. Particles in excess of 50 μm may feel gritty, so particle size is an important consideration. For solution products, due to the depression of freezing point by the soluble API, dose strengths of up to 60 mg are achievable. In both solution- and suspension-based products, the API is finely dispersed in the dried unit, contributing to rapid dispersion and smooth mouthfeel.

In addition to the basic structure-forming components and API, other excipients may be included in the formulation such as pH-modifying agents for optimal stability or taste-masking effect, and flavors and sweeteners for palatability. If necessary, other taste-masking strategies such as complexation with ion-exchange resins or encapsulation of the API may also be considered, though the larger particle sizes and need to maintain the integrity of taste-masked particles during the mixing and dosing steps are more challenging with this technology.

The active mix is dispensed into preformed blister packs, which travel through a tunnel cooled with liquid nitrogen to freeze the product rapidly. After freezing, the product is lyophilized, and the dried blisters are sealed.

Figure 1: Cross-section of a lyophilized ODT showing the highly porous structure. (FIGURE COURTESY OF THE AUTHORS)
The freezing process results in a network of ice crystals that are sublimed during lyophilization to produce a highly porous structure (see Figure 1). The matrix components maintain the structure of the dried unit, but on contact with moisture, the high porosity leads to rapid penetration of water. The matrix quickly dissolves, resulting in the fast disintegration characteristics of Zydis products. In vitro disintegration times of less than 10 s are typical of Zydis products and are clearly well within the FDA ODT guideline of 30 s.


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