Yingtai: Freeze-Drying Mini Lecture | Freeze-Dried Fast-Dissolving Preparations
Oral Disintegrating Tablets (ODTs) are a special type of tablet that can rapidly disintegrate, disperse, or dissolve in the oral cavity with little or no water. Patients only need a few swallowing motions to complete the dosing process, offering advantages such as convenience of administration. There are various methods to prepare ODTs, including freeze-drying, molding, and compression. Among these, the freeze-drying method is the earliest technique used to prepare ODTs, and tablets produced this way are called freeze-dried fast-dissolving tablets.
Basic Principles
The principle of vacuum freeze-drying in preparing ODTs involves suspending the drug in a solution, rapidly freezing it into a solid, and then removing water via sublimation under vacuum, bypassing the liquid phase. The resulting product has a porous, sponge-like structure, allowing rapid water penetration and disintegration within seconds, enabling administration without water.
Requirements for the drug substance in freeze-drying fast-dissolving preparations:
1. Generally suitable for insoluble drugs (<400 mg) or water-soluble drugs (<60 mg). Large-dose water-soluble drugs are unsuitable because they may not freeze completely, leading to melting during drying, which can cause structural collapse and affect product quality and yield. Water-insoluble drugs can be used in larger doses, but smaller doses are preferred—the lower the drug content, the higher the porosity, leading to faster absorption and dissolution.
2. The drug should exhibit chemical stability in aqueous media to prevent degradation or structural changes before drying.
3. Small particle size is required. Larger particles may cause sedimentation in the suspension, leading to uneven filling, dose inaccuracy, and poor uniformity. Additionally, the drug should be tasteless to minimize the need for flavoring agents. Drugs with high bitterness, large doses, or high melting points are generally unsuitable, though techniques like powder coating, micronization, or suspension stabilization can mitigate these issues.
Key Features
Freeze-dried fast-dissolving tablets offer:
- Rapid dissolution (within seconds)
- No need for water
- Enhanced drug stability and bioavailability
- Ideal for emergency, pediatric, and dysphagic patients
1. Ease of Administration & Improved Patient Compliance
- Disintegrates in 5–15 seconds, eliminating the need for water—ideal for children, elderly, bedridden patients, and those with swallowing difficulties.
- Unlike conventional tablets or capsules, which may linger in the esophagus, ODTs dissolve instantly, reducing choking risks.
- Can also be administered sublingually, making them useful for **field workers or desert environments.
2. Rapid Absorption & High Bioavailability
- The drug is dispersed as fine particles in a porous matrix, allowing rapid absorption through oral mucosa and bypassing first-pass metabolism, leading to faster onset and higher bioavailability.
3. Gastric Mucosal Protection
- Studies show that freeze-dried ODTs distribute more evenly in the stomach compared to conventional tablets or liquids. Their fine particle size and low liquid volume allow uniform adhesion to the gastric mucosa, potentially offering protective effects.
Despite its advantages, freeze-drying requires large-scale equipment, long production cycles, and high costs. Additionally, disintegration time and friability are highly dependent on matrix materials, concentration, and freezing conditions, and standard packaging may not suffice.
Common Excipients
1. Matrix Materials (e.g., gelatin, arabic gum, HPMC, pectin, dextrin, alginates) – Provide structural support. Gelatin is commonly used to form a glassy amorphous structure.
2. Sugars & Polyols (e.g., mannitol, sorbitol, lactose, cyclodextrin, dextran) – Enhance stability, hardness, and dissolution rate. Mannitol is preferred for its cooling effect.
3. Suspending Agents (e.g., xanthan gum, acacia gum) – Ensure uniform drug distribution. Xanthan gum (0.001–1%) can act as a flocculant with gelatin.
4. Others – Wetting agents (e.g., ethanol), colorants (e.g., iron oxides, 0.08–3 mg/tablet), flavors, preservatives, permeation enhancers, and pH adjusters (to enhance transmucosal absorption).
Manufacturing Process (Example: Zydis Technology)
1. Formulation – The drug is dissolved/suspended in water, then dosed into pre-formed blister pockets.
2. Freezing – Rapidly frozen at -40°C to form a uniform ice crystal network. Controlled gradient freezing (e.g., -5°C for 1h, then 1°C/min to -40°C) prevents large ice crystals.
3. Primary Drying (Sublimation) – Under vacuum (<0.1 mBar), temperature is slowly raised to -20°C to 0°C to sublimate ice. Critical to stay below the eutectic point (Tg’) to avoid collapse.
4. Secondary Drying (Desorption) – Temperature increased to 20–30°C to remove bound water (residual moisture ≤2%). Online monitoring (e.g., dew point sensors) ensures stability.
Key Controls:
- Eutectic point measurement (Differential Scanning Calorimetry)
- Vacuum leak testing
The final product has 80–90% porosity, enabling disintegration in 5–30 seconds upon contact with saliva.
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Note: Water-soluble drugs may form easily soluble films or low-eutectic mixtures, complicating freeze-drying. Drugs can be added before or after matrix formation, with non-aqueous solvents used for moisture-sensitive drugs.
