Solid-State Characterization and Dissolution Properties of Lovastatin Hydroxypropyl-β-Cyclodextrin Inclusion Complex

The objectives of this study were to prepare and characterize inclusion complexes of lovastatin with hydroxypropyl-β-cyclodextrin (HPβ-CD) and to study the effect of the complexes on the dissolution rate of lovastatin (LVS). The findings suggest that LVS's poor dissolution profile can be overcome by preparing its inclusion complex with HPβ-CD.
Feb 02, 2007



Lovastatin (LVS) is a well-known compound for lowering plasma cholesterol levels. After oral administration, the inactive parent lactone is hydrolyzed to the corresponding hydroxyacid form. The hydroxyacid is the principal metabolite and a potent inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase. This enzyme catalyzes the conversion of hydroxymethylglutarate to mevalonate, which is an early and rate-limiting step in cholesterol biosynthesis (1, 2).

LVS is white crystalline powder that is insoluble in water (0.4 g/mL). At room temperature, the partition coefficient of LVS in n-octanol/water system is approximately: Ko/w = 1.2 × 104 (3). Low aqueous solubility of LVS leads to inadequate dissolution in gastrointestinal fluids and, hence, poor absorption, distribution, and targeted organ delivery. The improvement of aqueous solubility in such a case is a valuable goal to improve therapeutic efficacy.


Figure 1: The structure formula for the β-cyclodextrin molecule.
Cyclodextrin (CD) is a cyclic (α-1, 4)-linked oligosaccharide made of α-D-gluco-pyranose units (see Figure 1). Hydroxypropyl-β-cyclodextrin (HPβ-CD) is more water soluble than the parent molecule and has hydroxypropylester groups attached to the hydroxyl groups in position 2. The molecule has a cone-like configuration with a hydrophilic surface and a lipophilic cavity. In this cavity, hydrophobic molecules interact with lipophilic molecules without forming any covalent bonds and can produce so-called "inclusion complexes," which increase the water solubility and stability of the drug substance (4–6). Complexation with CDs has been reported to enhance the solubility, dissolution rate, and bioavailability of poorly water-soluble drugs. CDs first gained attention in marketed products as drug delivery technologies that enabled the development of various prostaglandins (7). The inclusion complex of rofecoxib/HPβ-CD (1:1 molar ratio) was prepared by Baboota et al. using a kneading method with a subsequent improvement in dissolution caused by amorphization (8). Several other drugs such as ganciclovir, nimesulide, itraconazole, and tolbutamide have been tested for CD inclusion to enhance solubility (9–12).

β-CD has ideal dimensions to complex a range of commonly used drugs. Unfortunately, it has the limitation of a high affinity for cholesterol, which may lead to crystallization of a poorly water-soluble β-CD–cholesterol complex in the kidney. This complex could cause nephrotoxicity. HPβ-CD, a chemical derivative of β-CD, similarly improves the aqueous solubility of many drugs, but it is more hydrophilic than β-CD, forms a less-stable complex with cholesterol, and, therefore, is less toxic (13).