Sterile crystallization

Many dry solid parenteral products, such as the cephalosporins, are prepared by sterile crystallization techniques. Control of the crystallization process to obtain a consistent and uniform crystal form, habit, density, and size distribution is particularly critical for drug substances to be utilized in sterile suspensions. For example, when the crystallization process for sterile ceftazidime pentahydrate was modified to increase the density and reduce the volume of the fill dose, the rate of dissolution increased significantly. 

In the first example, procaine penicillin, an aqueous vehicle containing the soluble components (such as lecithin, sodium citrate, povidone, and polyoxyethylene sorbitan monooleate) is filtered through a 0.22 pm membrane filter, heat sterilized, and transferred into a presterilized mixing-filling tank. The sterile antibiotic powder, which has previously been produced by freeze-drying, sterile crystallization, or spray-drying, is aseptically added to the sterile solution while mixing. After all tests have been completed on the bulk formulation, it is aseptically filled. 

SVI formulations are relatively simple, composed of the active ingredient, a solvent system (preferably aqueous), a minimal number of excipients present for reasons described later in this chapter, and the appropriate container and closure packaging system. If the active ingredient is unstable in solution or suspension, the product can be a dry powder, processed either by lyophilization or by sterile crystallization. 

Examples in this chapter include sterile crystallization of a labile compound, yield enhancement by crystallization, yield and selectivity enhancement, removal of low-level impurities via crystallization from the melt, crystal formation in vials in a freeze drier, and non-equilibrium resolution of stereoisomers by crystallization. These examples represent unique crystallization processes designed for specific purposes. One lesson to be learned from examination of these nonmainstream applications is that understanding of principles can lead to inventive solutions to problems. For instance, in Examples 11-2 and 11-3, the solubility difference between starting material and desired product is used to optimize the reaction yield/selectivity by crystallizing the product and protecting it from overreaction. 

While solution crystallization is the main focus of this book, there are applications which are special cases of the CrystaUization methods described in earher chapters. For example, a process requiring sterile crystallization is a special example of an antisolvent addition and is presented in Example 11-1. In this particular example, it is necessary to produce fine particles in order to meet drug dissolution time specifications in the final single-dose vials. Furthermore, the material is thermally unstable. Therefore, special precautions have to be taken to minimize any degradation during processing. 

Fig. 5. Fermentative production of amino acids (140). A, pure culture B, inoculation C, boiler D, air compressor E, air filter F, seed tank G, ammonia water for pH control H, fermenter I, sterilizer , culture media K, preparation tank L, centrifugal separator M, ion-exchange column N, crystallizing...

Where free chlorine is present, eg, in drinking water, it is measured on-site, and a crystal (eg, 10 mg/40 mL) of sodium thiosulfate is added to the botde prior to sterilization to convert free chlorine to chloride. 

To two liters of a culture so prepared there is added under sterile conditions a solution of 500 mg of 17a-methyl-testosterone in 15 cc of acetone. Shaking is carried out for 3 days at 27°C, the mycellium then filtered off with suction, washed with water and ethyl acetate and the combined filtrates extracted with ethyl acetate. The extraction residue obtained after evaporation of the solvent is dissolved in a little acetone. On addition of ether, the 1-dehydro-17a-methyl-testosterone is obtained in compact crystals. MP 163° to 164°C. 

The effects of acid rain are particularly severe in areas where the bedrock is granite or other materials incapable of neutralizing H+ ions. As the concentration of acid builds up in a lake, aquatic life, from algae to brook trout, dies. The end product is a crystal-clear, totally sterile lake. 

Various drugs are known to exist in different polymorphic forms (e.g., cortisone and prednisolone). The rate of conversion from a metastable into the stable form is an important criteria to be considered with respect to the shelf life of a pharmaceutical product. Polymorphic changes have also been observed during the manufacture of steroid suspensions. When steroid powders are subjected to dry heat sterilization, subsequent rehydration of anhydrous steroid in the presence of an aqueous vehicle results in the formation of large, needle-like crystals. A similar effect may be... 

To obtain a uniform product from lot to lot, strict adherence to the procedures developed for a particular crystallization must be followed, including control of pH, rates of addition, solvent concentrations and purity, temperature, and mixing rates. Each crystallization procedure has to be designed to ensure sterility... 

Two basic methods are used to prepare parenteral suspensions (a) sterile vehicle and powder are combined aseptically, or (b) sterile solutions are combined and the crystals formed in situ. Examples of these procedures may be illustrated using Penicillin G Procaine Injectable Suspension USP and Sterile Testosterone Injectable Suspension USP. 

An example of the second method of parenteral suspension preparation is testosterone suspension. Here, the vehicle is prepared and sterile-filtered. The testosterone is dissolved separately in acetone and sterile-filtered. The testosterone-acetone solution is aseptically added to the sterile vehicle, causing the testosterone to crystallize. The resulting suspension is then diluted with sterile vehicle, mixed, the crystals allowed to settle, and the supernatant solution siphoned off. This procedure is repeated several times until all the acetone has been removed. The suspension is then brought to volume and filled in the normal manner. 

Aseptic Crystallization and Dry Powder Filling. Aseptic crystallization is primarily used for manufacture of sterile aqueous suspensions. However, if the physical form of the drug is critical to quality of the final product, better control over physical form can be attained by aseptic crystallization because a large variety of organic solvents can be used to control the crystallization process. In aseptic crystallization, the drug is... 

Aqueous suspensions are prepared in much the same manner, except that before bringing the batch to final volume with additional sterile water, the solid that is to be suspended is previously rendered sterile by heat, by exposure to ethylene oxide or ionizing radiation (gamma or electrons), or by dissolution in an appropriate solvent, sterile filtration, and aseptic crystallization. The sterile solid is then added to the batch, either directly or by first dispersing the solid in a small portion of the batch. After adequate dispersion, the batch is brought to final volume with sterile water. Because the eye is... 

In this level, the fundamental tasks required to convert the raw materials into the final product are identified. All tasks are related to property differences. Siirola (1996) has presented the following hierarchy of property differences molecular identity, amount, composition, phase, temperature/pressure, form. This list of tasks is not very well suited for food properties. Common tasks for food processes are decontamination (e.g. pasteurization and sterilization) and structure formation (e.g. emulsification, size reduction of dispersed phase in an emulsion, crystallization, interfacial adsorption/desorption). 

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