Microspheres manufacture methods

Microspheres are small and have large surface-to-volume ratios. At the lower end of their size range they have colloidal properties. The interfacial properties of microspheres are extremely important, often dictating their activity. In fact, the principle of microsphere manufacture depends on the creation of an interfacial area, involving a polymeric material that will form an interfacial boundary and a method of cross-linking to impart permanency. The methods of manufacturing described later are by no means comprehensive and the reader should bear in mind that if the aforementioned criteria are adhered to, the only limitation to the manufacture of microspheres is the researcher s imagination. 

This is one of the earliest methods of microsphere manufacture. The polymer and drug must be soluble in an organic solvent, frequently methylene chloride. The solution containing the polymer and the drug may be dispersed in an aqueous phase to form droplets. Continuous mixing and elevated temperatures may be employed to evaporate the more volatile organic solvent and leave the solid polymer-drug particles suspended in an aqueous medium. The particles are finally filtered from the suspension. Fig. 3 shows polylactic acid particles prepared in this manner. ... 

The wide spread and popularity of the emulsion solvent removal method in microspheres manufacturing are attributed to its inherent simplicity, operated in most cases at room temperature and normal atmospheric conditions. However, the physicochemical phenomena governing this process are complex due to the existence of a considerable number of processing and formulation parameters that profoundly affect the properties of the product obtained. The following formulation and processessing parameters greatly influence the microspheres products ... 

With a manufacturing method (or MEH method), deformation mechanisms in the presence of compressive residual stress around particles in relation with the toughening conditions, relative stress components, and fracture morphology have been analyzed using Mohr circles. A major difference in deformation between MEH and non-MEH methods was found to be in the location of plastic deformation under plane-strain. The plastic deformation of non-MEH was dominantly in matrix and appeared in the form of matrix cavitation. In the case of MEH, it was dominantly in microspheres. It was suggested that compressive residual stress promotes plastic deformation of microspheres caused by extrusion effect. 

A recent achievement worthy of note is the manufacture of microspheres containing an inert gas, e.g. nitrogen, or a volatile liquid, such as the freons The patent literature contains methods for producing microspheres based on poly(vinyl chloride) and poly(divinyl chloride), containing isobutane or carbon tetrachloride 52>, and based on poly(methyl methacrylate), containing neopentane . Microspheres containing liquid dyes and oils are also used to make syntactic foams 58>. 

Spherical particles proved to be superior in several applications owing to their favorable properties. Thus, they are used in thermal spraying for their excellent flowabil-ity, in powder metallurgy because of their excellent reproducibility in manufacturing parts with controlled porosity and as a filler material, as well. Metal microspheres can be easily produced by melt atomization. Similar method in the case of ceramics is impractical. Micron-sized ceramic particles, however, can be smelted by thermal plasmas that provide exceptional conditions for spheroidization due to its high temperature. In terms of purity and residence time of the particles in the hot temperature core, RF plasmas provide better conditions as compared to arc plasmas. 

The characteristics of microspheres containing drug should be correlated with the required therapeutic action and are dictated by the materials and methods employed in the manufacture of the delivery systems. 

Rather conventional means for the manufacturing of hollow microspheres with diameters between 1 and 1000 pm have been developed [11.9]. Methods include spray drying and dripping as well as emulsion or suspension techniques. The microspheres feature low effective and bulk densities coupled with high specific surfaces. Typical wall thicknesses are in the range 1-10% of the diameter. Potential wall materials include glass, ceramic and mixed oxides, silicates and aluminosilicates, polymers and polycondensates, and metals. Surface phenomena, which may be modified by chemical reactions, additives, and/or post-treatments, play an important role for microsphere formation, properties, and stability. Fig. 11.12 is the photomicrograph of a calcined hollow microsphere [11.9]. 

Method of piastisoi manufacture and use determines final product density. Making a piastisoi composition comprising a thermoplastic resin, a plasticizer resin, inert filler, and hollow thermoplastic microspheres should consider the following points ... 

The manufacturer s User s Manual (Sirtex User s Manual issued March 2002, pp 38-42) suggests three methods of estimating the activity to use for resin microsphere treatment (6.4.3.1) BSA method. 

Fig. 6.1. Typical tumor volume and distribution in metastatic cancer to the liver. Resin microsphere radiation activity planning can be performed via two of the three methods recommended by the manufacturer. The distribution of disease is such that the third method - the partition method - is not valid in this case...

The prescribed activity estimated by the Body Surface Area method for resin microspheres is more consistent with the delivered dose in clinical practice and therefore should be the method of choice. For glass microspheres, the prescribed activity calculation method described by the manufacturer is recommended. 

The other important elements in the engineering of a process to produce microspheres are the reproducibility, scalability, and aseptic operation of the process. The overall process must yield microspheres with the same characteristics from batch to batch. As there are a number of variables in the process (as listed in Table IV), the reproducibility of the overall process may be quite difficult to achieve. However, only a few variables are critical to the final microsphere characteristics, and, thus, if these variables are well regulated, the process should reproducibly manufacture the desired microspheres. One consideration often neglected by developers of novel methods for encapsulation is the scalability of the process. Many processes... 

Microcarrier culture has proven to be the most effective scale-up method for ADC, despite its limitations (critical procedures, low surface area-to-volume ratio of a sphere). To increase the surface area porous particles were developed. The initial particle was the Verax microsphere which was 500 fim in diameter and manufactured from bovine collagen. The interconnecting channels of 20- to 40- u.m diameter provided an internal open volume of 80% of the sphere. The spheres were fluidized at 75 cm/min upward flow, and cell densities in excess of 10 /mL intrasphere volume were achieved (equivalent to 4 x 10 /mL in the bioreactor). The sphere matrix provided a huge surface... 

---