Solid Solutions

Solid solutions are homogeneous, single-phase systems in which the components are completely miscible with one another, on a molecular scale, in the solid state. In Figure 5, if a molten mixture of A (drug) and B (carrier) is cooled from point

Figure 5 Phase diagram illustrating the formation of a solid solution when a molten mixture of drug (A) and carrier (B) is cooled; a certain fraction of carrier could remain dissolved in drug (region defined by a) and certain fraction of drug could remain dissolved in carrier (region defined by ¡). The dotted line represents solidus curve when the liquid completely converts into solid form.

Figure 5 Phase diagram illustrating the formation of a solid solution when a molten mixture of drug (A) and carrier (B) is cooled; a certain fraction of carrier could remain dissolved in drug (region defined by a) and certain fraction of drug could remain dissolved in carrier (region defined by ¡). The dotted line represents solidus curve when the liquid completely converts into solid form.

F to below its liquidus curve (defined by point D on line XY), the drug will begin to precipitate in the molten carrier as either a crystalline or amorphous solid. During such precipitation, it is possible for a fraction of carrier to remain molec-ularly dispersed with the precipitating drug. Similarly, solid solution of drug in carrier can result if mixture at point L is cooled below its solidus curve (point G). The fraction of drug that remains dissolved at G is given by point I. When the two-phase mixture of solid solution (segmented zone) and liquid solution of drug-in-carrier is cooled further, the concentration of drug in solid solution increases. Upon further cooling below the line JK, the two solid phases begin to separate out as the a-phase, which is the saturated solid solution of carrier-in-drug and the ¡-phase, which is the saturated solid solution of drug-in-carrier.

Unlike metallic alloys, pharmaceutical melts typically do not form crystalline solid solutions. In the case of polymers such as PEG and polyethylene oxide (PEO), which are semi-crystalline, solid solution formation is rare but the possibility cannot be ruled out, since the semi-crystalline nature of such polymers can permit drug to remain entrapped as a solid solution in the polymer amorphous regions. Amorphous solid solutions have been described in the pharmaceutical literature using polymers such as polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), and alike (23). A solid solution is believed to exist in the amorphous mixture if there is a composition-dependent change in the glass transition temperature (Tg) of the drug-excipient mixture (24).

Although drug-carrier miscibility in the solid state can help to enhance the drug dissolution rate and possibly, the bioavailability, the physical stability of the solid dispersion under conditions of elevated temperature and humidity is of concern. Drug-carrier phase separation and drug crystallization can result in a reduction in the drug release rate. One obvious approach to minimize such drug crystallization is to experimentally identify a drug concentration, which would not result in crystallization upon storage. This drug concentration is referred to as the "apparent solid-solubility" and has been determined using thermal analysis and X-ray diffraction (25-27).

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