A partially freeze-dried lyophilization technology for producing fast-melting tablets

September 1, 2007
Kurt H. Bauer
Pharmaceutical Technology Europe
Volume 19, Issue 9

A new economical method for producing fast-melting lamina-like dosage forms.

Fast-melting lamina-like dosage forms — tablets that quickly dissolve or disintegrate — are becoming popular. Several types of these fast-melting tablets exist and this new peroral dosage form has already been admitted into the European Pharmacopoeia (EP) as a monograph.1

The different types of these new dosage forms are produced using a variety of manufacturing methods.2 The most rapidly dissolving and, therefore, the fastest drug-releasing tablets are produced by the Zydis freeze-drying process.3 The internal structure of these freeze-dried lamina-like dosage forms is comparable to lyophilized parenteral dry injections. Under the microscope their structure looks highly spongy and resembles an assembly of tiny solidified bubbles (Figure 1a).

Figure 1

Externally, their shape is similar to a tablet, but that is where, in principle, the similarity ends; unlike tablets, they are not produced by compression, but by pouring out the individual doses as a liquid into the moulds of blister packs (pull-off packs). These are then solidified by freeze-drying in the moulds, thus negating the need for a tablet compression machine. However, there are serious drawbacks associated with this in terms of time and energy consumed, particularly for deep-freezing and drying under high vacuum conditions. There is much interest in finding a cheaper alternative to produce this type of tablet, but a solution has been elusive.

Freeze drying or lyophilization processes normally consist of three stages: deep freezing from –40 °C to –50 °C, the main drying step and the final drying step. The drying curve of these processes show that the initial deep freezing step is energy intensive and highly dependent on the temperature transfer from the heating and cooling plates to the product. It is, therefore, important at this stage to optimize the temperature transfer. The main drying step consumes most of the time and energy because the drying temperature must always be maintained below the eutectic temperature for a relatively long time — under a high vacuum — until almost all of the water has sublimed.

This requirement limits the possibilities of improving this process. Saving time and energy in high vacuum is almost impossible and the eutectic temperature is specific for each product. A small improvement can be achieved by scavenging air to remove the evaporated humidity slightly faster from the freeze dryer. However, the product must always be kept deeply frozen during the main drying step.

The amount of water to be sublimed plays a decisive role in relation to the drying time. The amount required is relatively high for freeze-drying procedures and cannot usually be modified without accepting certain disadvantages.

Nevertheless, we decided to explore this route further by investigating the possibility of developing a partial or reduced freeze-drying method where only part of the entire dose of the solid components is dissolved in water (i.e., only those components that must be dissolved in water to be pharmaceutically effective).

Dividing the solid component.

The solid component can be divided into different portions. The powdered dose part is the first portion to be poured into the mould of a blister pack (or another suitable container). This portion is partly composed of those components that do not need to be dissolved because of technological or biopharmaceutical factors.

The remaining components are then added in liquid form. This solution or partial suspension also contains suitable binding agents to achieve sufficient firmness. The liquid part may contain other components that develop their optimal biopharmaceutical or technological effects in solution. The APIs can be added undissolved with the solid part, as well as dissolved with the liquid part, depending on the absorption properties required. That means, the addition of a dissolved API preferably leads to fast and complete absorption, while the absorption of undissolved incorporated drugs results in a more or less retarded absorption. But, for instance, the absorption properties can also be controlled or adjusted beyond this by using preprocessed pellets, for example, with intestinal soluble coatings (Figure 2).

Figure 2

The proportion of liquid to solid components is adjusted in such a way that the liquid sufficiently fills the interspaces in the powder charge. The structure of the final product is similar to a mortared stone wall (Figures 1b and 2). The stones of the wall symbolize the solid powdery formulation parts and the network-like mortar layers symbolize the freeze-dried liquid parts added later.

Unlike complete freeze-drying, which cannot be avoided if complete lyophilization is required, only a small volume of the liquids is frozen and dried for this partial or reduced freeze-drying process, which is called the LyoPan process.4 The amount of water used by this method is considerably less (about 40–70%), which results in corresponding savings in production time and energy consumed. There are no technological disadvantages of the final product produced by this method.

The freeze-dried, three-dimensional 'network-like' structure, which holds the solid matter particles together, disintegrates almost as quickly as an entirely freeze-dried body. The firmness of the final product is not impaired because the solid components retain their natural firmness and are finally bonded together by the network-like and freeze-dried connecting structure.

Instruments and methods

The materials used for these new dosage forms were similar to those required for Zydis products and other fast-melting tablets. This is important for the registration and the admission of new drug products. Some other ingredients were also required. The most important difference between traditional methods and this complementary new technology is that the amount of water is reduced drastically, whereas the amount of undissolved structure-forming materials is increased proportionally.

This new method combines blister packaging machines with freeze-drying units. Because the moulds of the blister packs are conventionally only filled with liquids for the production of Zydis products, the blister packaging appliances for the complementary new production technology also require an additional powder dosing device. These combined solid–liquid dosing devices are simple to use at the development and experimental stages. Because the intermediate products are semisolid or pasty — and not liquid — they cannot be spilled and are easier to handle, particularly for automatic charging.

Developing a basic formulation

A basic formulation using this new technology can use manifold pharmaceutically suitable excipients, preferably those monographed in the EP.

The compositions in Table 1 are in milligrams per dosage form and in grams for an experimental batch. Part 1 is the powdered part and Part 2 is the liquid part. These new formulations can be adapted for different applications and to achieve specific qualities.

The solid formulation in Part 1 usually consists of a structure-forming agent (e.g., mannitol), a fluidizing agent (e.g., Aerosil 200; Degussa, Germany) and a super disintegrant (e.g., sodium starch glycolate; JRS Pharma, Germany and AVEBE, The Netherlands). A wide range of excipients can be used for this process. Sugars, salts and polymers are suitable structure-forming agents, as well as glycine or pregelatinized starches. Completely or partially preprocessed active substances — such as coated particles, crystals and even pellets — can be incorporated into this new technology. For example, a stick-shaped bag with high-dose pellet filling can be reformulated into a fast-disintegrating solid single-dose product (Figure 3). Although this dosage form disintegrates fast, the incorporated preprocessed pellets may release their drug retarded or in an otherwise controlled way.

Figure 3

The liquid formulation in Part 2 in Table 1 contains suitable binding agents (e.g., gelatines or povidones, a wetting agent such as Poloxamer [BASF AG, Germany] and a small amount of the structure-forming agent in dissolved form). In this case, the drug substance can be added with the liquid part. However, it is possible to incorporate the drug substance with the powdered part without any problem. It depends on the intended or optimal bioavailability.

Table 1 Composition of powdered portion (Part 1) and liquid portion (Part 2) for a tablet and for an experimental batch prepared using the LyoPan process.

In the example shown in Table 1 the powdered formulation part was 76 mg and the liquid one was 84 mg. An additional 26.5 mg of solid matters in a dissolved state are contained in the liquid part. This means that the amount of water to be removed by sublimation is reduced to 57.5 mg or 57.5 μL for this example. This amount corresponds to approximately 36% of the entire filling weight of 160 mg. The spongy dosage form after drying has an average weight of about 102.5 mg.

The relationship between the solid and liquid parts can also change depending on the particle size of the inserted ingredients. The reduction of the amount of water to be removed by sublimation down to 36% represents a substantial saving in time and energy, because during normal freeze-drying 70–90% of water must be sublimed.

Comparing the drying curves of the old and new technology confirms the savings achieved by the new approach. In a production freeze-dryer with thermo-sensor instrumentation, optimized for parenteral vials and not for peroral dosage forms, the drying curves were determined under comparable conditions in a 24-hour drying operation for Formulation 1 and Formulation 2 (Table 2). Formulation 1 corresponds to the basic formulation listed above and Formulation 2 was prepared because the real compositions of commercial Zydis products were not known. Formulation 2 was a completely lyophilized formulation and contains approximately 90% of water.

Table 2 Formulation of tablets prepared by LyoPan (Formulation 1) and Zydis (Formulation 2) technology.

The data in the production-size freeze-dryer during the two parallel and concomitantly performed experimental series with Formulation 1 and 2 were continuously recorded (i.e., the particular pressure in the freeze-dryer; the temperatures at the utility spaces at, for example, the heating and cooling plates and the condenser; and in the three 2 mL vials with the 1.5 g product samples).

Every sample of both series was frozen at the beginning for 2 h at –45 °C and a normal pressure of 1000 mbar was applied. The main drying step was then immediately started, and for 1 h, a vacuum of 0.09–0.1 mbar was applied. In the following hour, the utility space temperature of –40 °C was increased to the main drying temperature of –20 °C. The eutectic temperature of Formulation 1 and Formulation 2 was –5 °C and 0 °C, respectively. The main drying temperature represents the eutectic temperature plus a certain safety surcharge, in this case about –15 °C to –20 °C. These conditions, within the framework of main drying, were retained for 14 h.

After 2.5 h, the utility space temperature was raised from –20 °C to +20 °C. The last step was the final drying for 2 h at 20 °C and a vacuum of <0.02 mbar. The temperature curves of the three product samples in the vials in every series ran narrowly side-by-side and virtually parallel to the utility space temperature, but were slightly higher. It is interesting to note that the product sample curves of Formulation 2 showed crossing after 10–14 h, and those of Formulation 1 after 6 h. From our experience, these overlaps show that the bulk of the moisture has sublimed. It is, therefore, safe to begin final drying at this point. The results indicate that the main drying step can be reduced to about 6 h with this approach. Further experimentation could possibly reduce the drying times to 2 h. This means that the main drying step can be performed in less than the duration of a normal work shift of 8 h.

The dimensions of the porosity of freeze-dried dosage forms depend mainly on the amount of water incorporated and subsequently sublimed. The porosity of normal freeze-dried products lies within 70–90%, and that of the new partial freeze-dried dosage forms within 30–50%. In spite of this reduced porosity, the disintegration qualities differ only slightly.

The new formulations can be optimized further for different purposes. For example, taste-improving components and sweeteners can be added. Further improvements may be obtained by optimizing the equipment. The main drying step could be reduced to about 2 h with improved experimental-size freeze-dryers. The main improvements in the future should be more effective heat transfers between the blister packs, and the heating and cooling plates of the freeze-dryer. The reported experiments were conducted in freeze-dryers suitable and optimized for parenteral products.

Qualities of novel dosage forms

Although the experimental formulations described were performed with a single type of binding agent, they have a moderately satisfying firmness. The tablets can be ingested by the patients without problems, and they can also be removed easily from a 'peel-off' package. However, they are comparable to other peroral freeze-dried dosage forms using a simple 'finger test', but not with normal tablets in terms of hardness. A more objective test method of assessing these porous dosage forms is being investigated.

To compare the quality of their disintegration properties, the dosage forms were tested with a texture analyser method because the standard disintegration testing methods of the EP do not differentiate sufficiently for the fast oral disintegrating tablets (ODTs).5

The new dosage forms had a disintegration time of approximately 4 s compared with about 2 s for a commercial Zydis product. The results are represented in the Figures 4a and 4b. In both graphs, the slopes of the curves started without any delay and increased steeply. They do not show the shallow starting slope characteristic of dosage forms that are not freeze-dried and disintegrate completely within a few seconds.

The curve of the Zydis product (Figure 4a) is almost horizontal after dissolution, while the same part of the curve of the partial freeze-dried product (Figure 4b) still exhibits some upward steps. These are obvious because a certain amount of the remaining crystals or granules of the incorporated powder part. This demonstrates the excellent differentiating ability of the texture-analyser method. The thickness of the object determines how the punch works through the dosage form or a similar object during the texture-analyser measurement. Because the punch approaching the lying flat object starts measuring from the moment it touches the object's surface, it finishes as soon as the object is completely dissolved or disintegrated.

Figure 4


The LyoPan process of partial freeze-drying shows great potential for the production of fast-melting lamina-like dosage forms to a satisfactory quality. This approach consumes less time and energy than previous methods to produce fast-disintegrating tablets, thus making it more economical. The benefits of this method provide a stimulus for increased activity in this segment of the market.


We are very grateful to BASF AG (Ludwigshafen/Rhein, Germany) for LutrolF 68 and Kollidon; JRS Pharma GmbH (Rosenberg, Germany) for Vivastar P; Gelita AG, (Eberbach/Baden, Germany) for Gelita-Sol P; and to Staerkle & Nagler AG (Zollikon, Switzerland) for Prejel PA5.

I am also very grateful to Ingrid Müller of the Hochschule Albstadt-Sigmaringen, Studiengang Pharmatechnik, Sigmaringen (Germany) for performing the texture analyser analysis.

Kurt H. Bauer is a professor at the Institute of Pharmaceutical Sciences of the Albert-Ludwigs-Universität, Freiburg (Germany). He is also chair of pharmaceutical technology and biopharmacy and a member of the Freiburg Materials Research Centre (Albert-Ludwigs-University), which collaborates closely with Pantec AG (Möhlin, Switzerland).


1. European Pharmacopoeia, 4th Edition.

2. Orally Disintegrating Tablet and Film Technologies, 4th Edition (Technology Catalysts International Corporation, Falls Church, VA, USA, 2006).

3. H. Seager, J. Pharm. Pharmacol., 50(4), 375–382 (1998).

4. K.H. Bauer/Pantec AG, European Patent Application EP 04 105 381.0 (28 October 2004).

5. R. Bohnacker et al., Pharm. Ind., 67(3), 32–35 (2005).