Issue:March 2016

LYOPHILIZATION – The Key to Creating Acceptable & Effective Fast-Dissolving Oral Formulations


INTRODUCTION

There are some patient populations for whom a fast-dissolving dosage form is extremely advantageous. If a patient has difficulty swallowing medicine, compliance with treatment regimens is going to be a challenge. This is often the case at either end of the age spectrum, with children and geriatric patients particularly likely to struggle with swallowing tablets and capsules.

Those with dysphagia, nausea, and vomiting also pose problems in terms of keeping an oral dosage form down long enough to dissolve and get to work. Tablets and capsules can pose a challenge for psychiatric patients as well. They might have difficulty in swallowing, but even if swallowing the tablet is not a problem, they may be resistant to the idea of medication and conceal it in their mouth to spit out later.

In all of these situations, a rapidly dissolving oral formulation would provide a solution. If the dosage form disperses and is absorbed extremely rapidly, it is much more likely to be administered effectively, and patient care is improved. The technique of lyophilization is important in the development of drug formats that dissolve rapidly, and offer quick dispersion while being pleasant to take.

There are other advantages in terms of product positioning. Although products such as painkillers are not difficult for otherwise healthy adults to swallow, they take time to start working. Any condition that has a rapid, unpredictable onset, such as migraine or diarrhea, would benefit from a formulation that has an effect on their symptoms more rapidly. An additional benefit is convenience, as no water is required to take them.

A dosage form that is designed to dissolve in the mouth and be absorbed rapidly needs to meet a couple of key requirements. It must indeed disperse very quickly so that it does not hang around in the mouth and cause discomfort or fail to be absorbed effectively. Furthermore, if it is going to be acceptable to the patients, it must be palatable. A product that tastes unpleasant or has a disagreeable, gritty mouthfeel is unlikely to gain widespread acceptance however effective it may otherwise be.

LYOPHILIZATION IN FORMULATION

Lyophilization is the key to creating acceptable and effective fast-dissolving oral formulations. The process of lyophilization, or freeze-drying, starts with an aqueous solution or dispersion being frozen. The air pressure is then reduced by applying a vacuum, and the frozen water sublimes, going directly from ice to water vapor, thus removing it from the frozen solution. The result is a highly porous solid form with only a very low amount of residual water remaining.

If the lyophilization process is very carefully controlled, it can be used to tailor the dispersion or disintegration properties of a solid drug product. It can be applied to a wide range of pharmaceutical actives, resulting in palatable, orally disintegrating tablets that disperse quickly, with good mouthfeel.

The Zydis® orally disintegrating tablet has gained widespread acceptance since it was first introduced 30 years ago, and relies on lyophilization in its manufacture. Numerous drug formulations have reached the market since then using this technology, including drugs to treat Parkinson’s, schizophrenia, and anxiety disorders, as well as painkillers and antiemetics.

To make the tablets, the active ingredients are combined with a suitable carrier material comprising pharmaceutically compatible materials such as mannitol and gelatin. They are then either dissolved or dispersed in water using a standard mixer. The resulting liquid is dosed by weight into individual pre-formed blisters in a fully automated continuous filling process. This process requires accurate control and precision to ensure each dose contains the exact amount of active, and it is important that the suspension remains homogeneous throughout.

Once filled, the blisters are passed through a freezing tunnel cooled by liquid nitrogen. This freezes the water in the suspension ready for loading into low-temperature storage ahead of the freeze-drying process. Storing briefly in this way enables the filling to operate on a continuous basis ahead of the batch-wise freeze-drying process.

As soon as sufficient blisters have been filled and frozen, the lyophilization can begin, and they are transferred to the freeze-dryer. When the lyophilization is complete, the blisters are passed through a blister sealer, where they are sealed with aluminium foil or a suitable paper laminate. The sheets of blisters are cut to size, and the foil perforated to facilitate opening by the patient.

OPTIMAL MATERIALS & PARAMETERS

Selecting the optimal carrier materials is a crucial part of the development of a successful formulation. By selecting the correct grade of gelatin with the ideal dissolution profile, finished tablets that dissolve smoothly and rapidly in the patient’s mouth can be created. The mannitol is also important, and its ease of dissolution is key in creating a product with a pleasant texture, taste, and mouthfeel. The crystallization of the mannitol during the freezing process must be controlled if the resulting tablet is going to look good and have sufficient resilience and strength to survive the rigors of handling and transportation.

In production terms, the key difference between the Zydis process and a traditional freeze-drying operation is that in the Zydis process the blisters are frozen in a liquid nitrogen tunnel ahead of placement into the freeze-dryer. Normally, the freezing process takes place within the freeze-dryer. Separating the two is an important factor in the production of a tablet that disintegrates rapidly, and the material within the blisters must be completely frozen when the trays emerge from the tunnel.

The freezing process is controlled by a combination of the temperature within the tunnel, and how long the blister pockets remain within it. These two variables can be altered to give the ideal freezing rate for an individual tablet type. The faster the rate of freezing, the smaller the ice crystals will be. The resulting tablets will be stronger, but are also likely to take longer to disperse in the mouth. Smaller crystals can also hinder the rate at which the water vapor sublimes from the tablet during lyophilization, which can affect the efficiency of the drying process. Conversely, if the freezing process is slower, the ice crystals are likely to be larger. This will give tablets that disperse more quickly, but are likely to be less strong.

Creating the optimal balance between strength and speed of dispersion is the key to tuning the tablet’s delivery properties. Statistical experimental design can be used to determine the ideal freezing parameters, bearing in mind the desired properties and processing efficiency. Methods such as differential scanning calorimetry can be used to garner further information about important properties, such as the solution or suspension’s freezing and melting points.

When the freezing process is complete, the open blisters are stored within low-temperature cabinets to keep the contents frozen ahead of freeze drying. On the whole, the length of time over which they are stored usually has no bearing on the final product, but occasionally a specific storage period may be required. This applies to products that have high concentrations of a highly soluble drug or salts, which can inhibit the crystallization of the carrier materials, notably mannitol. Defining a minimum storage period in these cases ensures that there is sufficient time for any amorphous mannitol to become crystalline, and be less likely to shrink or crack.

CONTROL OF LYOPHILIZATION

The other crucial part of the manufacturing process is the freeze drying itself. The ice crystals formed during the controlled freezing are removed during lyophilization. This creates pores within the matrix of the freeze-dried tablet, as can be seen from the scanning electron microscope image in Figure 1.

While lyophilization is commonly used in pharmaceutical manufacture, it is more normally used to give a fixed amount of water within the product. With the Zydis process, it is crucial to control the way the ice crystals are formed and removed to create the characteristic porous structure. Instead of being stoppered or sealed during freeze-drying, in this process, they are permitted to equilibrate within a controlled environment when the lyophilization is complete. Thus, the product’s final water content is determined by a combination of the freeze-drying conditions, and also the intrinsic equilibrium moisture content of the various components of the formulation, and the relative humidity of the environment in which they are manufactured. This can be monitored using dynamic vapor sorption analysis, and a moisture content testing protocol such as Karl Fischer.

To achieve a good, stable structure, the ice crystals must be removed via sublimation as rapidly and completely as possible, without melting and forming water. The two most important parameters that must be controlled are the temperature of the shelf, and the drying time. Every individual formulation has its own characteristic collapse temperature, above which, that all-important porous structure will disappear, affecting the tablet’s disintegration time. It can also cause visible holes to be formed.

The temperature is controlled via heated shelves, which confer conductive, convective, and radiative heat. The more the temperature rises, the faster the drying occurs. Sublimation leads to rapid heat loss within the product, and therefore, it is much lower than that of the shelves, so the optimal temperature for the shelves may actually be higher than the tablet’s collapse point.

The maximum operating shelf temperature varies from product to product. The most effective way to determine this figure is via the inspection of finished products for defects resulting from collapse or melting as the process development is carried out. This is achieved by drying test batches over multiple cycles with different primary drying temperatures, and checking for drying-related defects in the products created. Analytical techniques, such as freeze-drying microscopy and differential scanning calorimetry, can also provide an insight.

It is important that the blisters remain under vacuum within the freeze dryer for a sufficient period to ensure all the ice is removed. Product quality is not at risk if it remains in the dryer for too long, but of course, this will have an impact on process efficiency as throughput will be reduced. It is possible to assess whether the drying has reached completion using techniques such as dew point sensors and pressure rise tests. Manual inspection of the finished product can also confirm dryness.

Process development for an orally disintegrating tablet made via Zydis technology is complex. It requires detailed knowledge of the material science underpinning the tablet structure, and how this affects the overall properties of the final dosage form. If these are not optimized to produce a stable tablet that disperses quickly and evenly, the product is unlikely to be a commercial success. The process harnesses the power of freeze-drying to remove water in a controlled manner to create matrices with defined and predictable properties, when used in combination with the optimal carrier materials. In this way, the aim of manufacturing oral dosage forms that disperse within 3 seconds with a pleasant taste and mouthfeel can be achieved.

SUMMARY

Multiple products are on the market made via this controlled lyophilization process. The fast-dissolving characteristics it can impart have enabled the demands of several challenging patient populations to be met with formulations of important medicines that work well for them. Convenience and fast onset of action can be combined with ease of administration, particularly for patients who struggle to swallow conventional tablets.

To view this issue and all back issues online, please visit www.drug-dev.com.

Leon Grother is Principal Scientist at Catalent Pharma Solutions in Swindon, UK. He earned his BSc in Pharmaceutical Science from the University of Greenwich, London, and his Masters in Industrial Pharmaceutical Science from the University of Manchester, UK. He has worked within R&D for more than 15 years, primarily on Catalent’s Zydis® ODT (orally disintegrating tablet) technology formulation and process development. During this time, he has gained expertise in freeze-drying and is a named inventor on several patents related to formulation of lyophilized dosage forms.

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