Excipients Used To Enhance Dissolution Of Biopharmaceutical Classification System Class Ii And Iv Drugs

In addition to controlling the site, the rate, and the duration of drug release, excipients can also be used to improve the dissolution of BCS class II and IV drugs in the gastrointestinal tract. Class II and class IV drugs have poor solubility and consequently incomplete dissolution and less than total release of the dose administered during the transit through the gastrointestinal tract.

The extent of drug release from oral solid formulations is determined by the dissolution rates of drug, which is a function of aqueous solubility and particle sizes as shown in the following equation.

h where D is the diffusion coefficient of a drug molecule in the dissolution medium; h, the stagnant layer surrounding the drug particle; S, the total surface area of drug particles; Cs, the saturated solubility of drug in the dissolution medium; and C, the concentration of drug in the dissolution medium. Obviously, there are two parameters for implementing strategies to enhance the dissolution of drug—one being the total surface area of drug particles and the other, solubility in the intestinal fluid. Pharmaceutical excipients can be used to manipulate drug solubility through various mechanisms, from changing the pH in the microscopic environment surrounding drug particles, to affecting the physical state of drug molecules packed with each other, to facilitating wetting by intestinal fluid, and to increasing solubility through emulsifying effects. Implementation of these strategic approaches requires a thorough understanding of the intrinsic characteristics of individual drugs, the desired formulation properties, the physicochemical properties of suitable pharmaceutical excipients, and the stability of drug molecules in the presence of pharmaceutical excipients in oral dosage forms.

Solid Dispersions/Solutions

Solid solutions (solid dispersions) of drugs and pharmaceutical excipients have received wide attention in recent years for enhancing solubility of poorly soluble drugs. There are two commonly used techniques of preparing the drug-excipient solid solutions: solvent method and hot-melt method (15,16). Pharmaceutical excipients can form solid solutions with drug molecules and change the physical state of drug particles from a crystalline state to an amorphous state, thereby facilitating drug dissolution. The amorphous state is not as orderly and tightly packed as the crystalline state, therefore the higher the number of amorphous regions in the solid solution, the quicker the dissolution and release of drug. It is conceivable that intermolecular electrostatic, hydrogen-bonding, or van der Waals interactions between pharmaceutical excipients and drugs will interfere with the orderly packing of drug molecules, resulting in a reduced degree of crystallinity in drug particles. With the aid of X-ray diffraction, it was observed that the relative amount of amorphous versus crystalline areas in drug particles depended on the quantity ratio of drug to excipient in the solid solution, which is determined by individual, unique physicochemical properties of drugs and excipients (15). The excipient:drug ratio is also responsible for the stability of the drug in an amorphous state. As the ratio is decreased, a formulation may have a higher propensity to crystallize over time during storage. Erratic crystallization over storage, and thereby change in performance is a key criterion used in development of solid solution-based formulations.

Griseofulvin, a BCS class II drug (Fig. 2), is a well-known example whose poor aqueous solubility causes low and erratic oral bioavailability. As shown below, gris-eofulvin has a hydrophobic molecular structure, and is practically insoluble in water. Its oral absorption is highly variable, ranging from 25% to 100%, depending on the crystal size. Ultramicrosize griseofulvin preparations were shown to have 100% oral absorption (12).

Application of pharmaceutical excipients to increase dissolution of griseofulvin from oral solid dosage forms and to increase its oral bioavailability has been well explored. In the solid solutions of griseofulvin with pharmaceutical excipients, such as PEG and HPMCP, amorphous griseofulvin rather than crystalline griseofulvin was found, offering an explanation of higher dissolution rates of griseofulvin resulting from solid solutions than from pure form (17,18). Amorphous griseofulvin dissolved much faster than crystalline griseofulvin. Formation of a eutectic mixture is another mechanism contributing to higher dissolution rates of the drug in the presence of pharmaceutical excipients (succinic acid) (19). Table 3 summarizes the effect of several hydrophilic excipients on the dissolution rate of the drug (17-22).

The principle of forming pharmaceutical excipient-drug solid solutions to enhance the dissolution of drug is applicable to a wide range of drugs regardless of their chemical nature being weakly acidic, weakly basic, or neutral. As shown in Table 4, the dissolution of BCS class II and IV drugs with a wide range of physico-chemical properties, including carbamazepine, furosemide, chlorothiazide, nifedipine,

Chemical Properties

Mefenamic acid Etoposide Piroxicam

Figure 2 Chemical structures of some of the drugs discussed in this chapter.

Mefenamic acid Etoposide Piroxicam

Figure 2 Chemical structures of some of the drugs discussed in this chapter.

nilvadipine, phenytoin, mefenamic acid, etoposide, and piroxicam (Fig. 2), were increased by pharmaceutical excipients (23-36).

With the aid of X-ray diffraction, it was observed that the formation of amorphous dispersion, instead of crystalline dispersion of drug, in the drug-excipient solid solution contributed to quicker dissolution and a higher amount of total drug release in the dissolution test. Furosemide (Fig. 2) was shown to form amorphous dispersions in the solid solution with either polyvinylpyrrolidone (PVP) or crospovidone, as evidenced by X-ray diffraction (26,27). The extent of amorphous dispersions

Table 3 The Effect of Hydrophilic Excipients on the Dissolution Rates of Griseofulvin (a Biopharmaceutical Classification System Class II Drug)





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