Secondary drying effects

Towards the end of main drying the data of Tice will systematically decrease this effect can be used for an automatic change from main to secondary drying (see Section 2.2.8). 

If these conditions are met, the curves as shown in Figure 1.78.1 are measured. Figure 1.78.3 shows one measurement and one repetition of this measurement and a third measurement with another product and other process data. Towards the end of main drying, the data on Tice will systematically decrease this effect can be used for an automatic change from main to secondary drying (see Section 2.6.2.2). 

For effective desorption, the chamber pressure should be sufficiently low at the terminal stage of secondary drying. A maximum acceptable pressure should be specified. 

While lyophilizing ampoules on trays under maximum vacuum, we have effectively observed a prolongation of primary drying by 20-30% under partial load conditions. However, in no case was an increase in product temperature noticeable, even when the transition ramp to secondary drying was started before completion of product primary drying. 

In horizontal validation, it is the time phasing of the segments at constant temperature that is varied. In its simplest form, horizontal validation consists of varying the duration of the terminal secondary drying step and examining the effects of this variation on sensitive properties such as residual moisture, bioac-... 

The decomposition of a compound labeled with a radioactive isotope can be due to one or more of four effects, as follows. (1) A primary (internal) radiation effect, wherein the decomposition of the molecules arises as a result of the disintegration of their unstable atomic nuclei. (2) A primary (external) radiation effect, in which decomposition occurs hy interaction of the molecule with a nuclear particle. (3) A secondary radiation effect, where decomposition arises from reaction with a reactive species produced hy the radiation. An example would he that of free radicals produced hy the radiolysis of residual water in freeze-dried carbohydrate samples. (4) A chemical effect, whereby decomposition arises from chemical reactions which are not connected with radiation. 

For C Maheled carbohydrates stored as freeze-dried samples under vacuum at room temperature, self-decomposition arises mainly hy the primary (external) radiation effect and the secondary radiation effect. However, it has been observed that the alkalinity of normally washed, Pyrex glass is detrimental to the stability of C -labeled carbohydrate sirups, and it is desirable to store the samples at as low a temperatiure as possible in order to reduce the rate of such unavoidable chemical reactions. 

It would appear that, for the freeze-dried samples of o-glucose (tubes 7-9), secondary-radiation effects play a major role in the decomposition, due probably to retention of non-bonded water by the n-glucose. Sucrose,... 

The importance of secondary-radiation effects may be seen from the decomposition of dextran-C sulfate containing about 20 D-glucose residues per molecule, observed by Bayly and Weigel. It had the relatively low specific radioactivity of 22.4 mC. per g.-atom of carbon (about 3 mC/ millimole of dextran sulfate). After three weeks in the freeze-dried form, it had charred and become a total loss. The decomposition was presumably attributable to a secondary-radiation effect arising from a prior liberation of sulfuric acid, which then released more sulfuric acid to destroy the material. 

Arising from the decomposition of C -labeled carbohydrates are an enormous variety of products. For example, when a sample of D-glucose-C (about 6 mg., having a specific activity of about 14.44 mC. per millimole) was stored as a freeze-dried sample in the dark for 26 months, a 14.5% decomposition of the D-glucose occurred and, by use of two-dimensional paper chromatography-paper electrophoresis, the presence of 37 constituents was revealed. The greater complexity of this system in comparison with that of 7-irradiated solutions of D-glucose supports the view that direct-action effects supplement the decomposition caused by secondary-radiation effects, which are entirely responsible for the decomposition when dilute solutions are irradiated. 

Two methods for reducing the magnitude of decomposition from primary (external) radiation are (a) dispersion over a large area and (b) dilution. These methods also reduce decomposition caused by secondary-radiation effects this is borne out by experimental results obtained with D-mannose-C. Aliquots (5 ml.) of pure o-mannose-C (about 100 /iC.) in water (100 ml.) were stored imder vacuum. By isotope-dilution analysis, it was estimated that the rate of decomposition in the freeze-dried state was 7 % a year and, in the frozen state, 1 % a year. The frozen state would, therefore, appear to be the most satisfactory method of storage over long periods of time. 

Secondary side effect An adverse reaction that is an indirect consequence of a drug s action but is nevertheless predictable (e.g., lowered potassium with diuretics, nausea with Digoxin, dry mouth with antidepressants). 

Although the process of unfrozen water removal from the material, subsequent to ice sublimation, is commonly referred to as desorption , this is misleading. It has been shown that the residual water forms a mobile component of a solid solution, so that diffusion more correctly describes the mechanism of its removal. Compared to the diffusion rate of water from the bulk to the surface, its eventual desorption from the surface is rapid and can in practice almost be neglected. As will be shown later, secondary drying kinetics can be modelled adequately by standard treatments of diffusive processes. The effects of many variables on the kinetics of secondary drying may be found in Pikal et al ... 

At the completion of primary drying, the water content of an amorphous product is sometimes expressed as JVg g water per g solid. The actual value, typically 0.3-0.5 g g is governed by details of the freezing process and will vary from product to product, or even from vial to vial. For most practical purposes, however, it may be assumed that the water content has little or no effect on secondary drying. This... 

Pikal et al studied a 5%-povidone (polyvinyl pyrrolidone, PVP) solution, dried from an 8-ml fill volume, of 2-cm depth, and from a 4-ml fill volume at a 1-cm fill depth. In this instance, the fill depth had little effect on the specific surface area of the dried product (2.5 m g compared to 2.3 m g )- It was found that the rates of secondary drying (as measured by the mean ratio of the (1 - F) values), the normalised water contents of the two products were essentially identical. A mean ratio of (1 - F) of 1.19 0.17 was found, indicating that cake thickness did not significantly affect secondary drying kinetics. It can thus be concluded that material at the top of the cake dries at a similar rate to material at the bottom, provided overheating is avoided. Similar experiments were carried out on an amorphous, formulated moxalactam product, as shown below. 

The protective effect is dependent on the process conditions. Especially the product temperature during secondary drying seems to be a critical parameter for survival. As the protective effect only occurs for low residual water contents when structural water is already removed, the water replacement mechanism may play a role in protecting cells from desiccation damage. In order to further investigate the mechanism of protection, pulsed NMR measurements were carried out to measure proton mobility of samples with and without added protectant. 

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