Supersaturation mechanism of drugs from solid dispersions with enteric coating agents.

Abstract

The crystallization behavior of drugs from supersaturated solutions containing carboxymethylethylcellulose(CMEC)was investigated to clarify the mechanism of supersaturation phenomena from solid dispersions with enteric coating agents in JP XI 2nd fluid(pH 6.8). Nifedipine,griseofulvin and spironolactone were used as drugs.The rate of crystallization of all drugs was remarkably inhibited by the presence of CMEC.It was found that the inhibition was not due to solubilization of the drugs by CMEC. The crystallization kinetics from supersaturated solutions suggested that the process of crystal growth itself was directly inhibited.Physical properties of the crystallized mass were also investigated in the case of nifedipine.It was thought that the inhibitory effect of CMEC on the drug crystallization was due to the adsorption of CM EC at the solid-water interface at the stage in which a hydrophobic drug crystal surface was formed,and further drug molecules could not deposit easily on the crystal surface for the following reasons;(1)formation of a step or kink,which is necessary for the crystal growth,was inhibited by polymer adsorption,and(2)molecular diffusion to the crystal surface was inhibited by the adsorbed polymer.Keywords-nifedipine;griseofulvin;spironolactone;solid dispersion;supersaturation;crystallization;crystal growth Chiou and Riegelman defined a "solid dispersion" as a dispersion of one or more active ingredients in an inert carrier or matrix in the solid state prepared by the melting(fusion), solvent,or melting-solvent method.2)It is well known that many drugs in solid dispersions are present as a high-energy amorphous phase and a solid dispersion using a water-soluble carrier shows supersaturation of a poorly soluble drug when the system is added to an aqueous medium.3)It can be considered that the dissolution of the drug takes place in the solid state prior to its exposure to the liquid medium.2) A few investigators have examined the dissolution mechanism of solid dispersions.4) However,quantitative analysis of the dissolution behavior in the amorphous state is quite difficult,since the amorphous state does not possess heat of fusion or solution,and this state transforms to the stable crystalline form easily during the experimental period.We attempted to apply a solid dispersion technique using different types of enteric coating agents as inert carriers to control the absorption behavior of water-insoluble drugs.5) Most of the drugs in these solid dispersions were amorphous,and the dissolution of the solid dispersions was practically nil in JP XI 1st fluid(JP XI disintegration medium,pH 1.2). However,they dissolved rapidly in JP XI 2nd fluid(JP XI disintegration medium,pH 6.8)and showed supersaturation phenomena.We also investigated the crystallization behavior of nifedipine(NP)from supersaturated solutions containing various polymers,6)since it was

Effect of polymer type on the dissolution profile of amorphous solid dispersions containing felodipine

“…However, the observation that solution levels remain higher than the equilibrium solubility value strongly suggests that the polymers are able to inhibit crystal growth. The inhibition of crystallization and crystal growth by polymers has been observed previously [29][30][31][32][33]. Thus it appears that the system has decreased in concentration to a level where nucleation is no longer spontaneous (i.e.…”

Discovering and Developing Molecules with Optimal Drug-Like Properties

“…Raghavan et al attributed the decreased crystallization rate of hydrocortisone acetate in polymer solutions to attractive forces between the polymer and the drug, e.g., by hydrogen bonding (Raghavan et al 2001). Hasegawa et al (1988) investigated ability of CMEC (carboxymethylethyl cellulose) to inhibit crystallization of nifedipine, griseofulvin and spironolactone from supersaturated solutions. The authors noted that the adsorption of CMEC on the surface of nifedipine crystals was the most important factor in inhibiting crystallization from supersaturated solution.…”

“…However, complete coverage, θ eq ¼ 1, is not considered to be a necessary condition for the complete prevention of crystal growth (Kubota and Mullin 1995). Polymer molecules inhibit the introduction of drug molecules from solution into the crystal lattice by occupying growth sites and thereby acting as a mechanical barrier (Hasegawa et al (1988). Several factors, such as hydrophobicity (Tian et al 2007;Zimmermann et al 2009), electrostatic interaction (Pan et al 2001;Tjipangandjara and Somasundaran 1991), and hydrogen bonding between the adsorbate and the interfacial species (Raghavan et al 2001;Somasundaran and Huang 2000;Somasundaran and Krishnakumar 1997) have been found to contribute to the adsorption process.…”

A Nifedipine Coground Mixture with Sodium Deoxycholate. II. Dissolution Characteristics and Stability

“…In general, the deposition process of a drug from a supersaturated solution depends on two factors: nucleation and subsequent crystallization (7,8). If the carriers used in the above techniques have a low inhibitory effect on drug crystallization, microparticulate crystals of the drug will precipitate from the supersaturated solution (2,9). However, this drug deposition process varies with the combination of drug and carrier.…”