Title

Physical stabilization of amorphous drugs by co-grinding with silicates

Date of Completion

January 2007

Keywords

Health Sciences, Pharmacology

Degree

Ph.D.

Abstract

Amorphous drugs, while more soluble, are often less preferred over their crystalline counterparts due to issues of poor chemical and physical stability. This, in turn, has reduced their commercial utility for oral solid dosage forms. It has been shown that reversion to the crystalline state is inhibited by co-grinding drugs with silicates. A number of mechanisms have been proposed for this phenomenon such as adsorption on the surface of silicate, capillary condensation of drugs in the silicate pores and formation of chemical bonds between drug and silicate. However, the exact nature of the interaction is not yet fully understood. An understanding of the nature of the interaction would allow prediction of successful amorphization, physical stability and dissolution enhancement of co-ground amorphous drugs. Further an understanding between various formulation as well as processing factors necessary for optimum stability is also needed to facilitate commercial utilization of this approach. ^ In this work a chemometric method based on ATR-FTIR was used to quantify crystallinity and to determine the physical stability of co-ground (drug-silicate) powders. Evaluation of formulation and processing parameters such as ratio of drug to silicate, processing humidity and time, and the nature of the silicate (i.e., surface area, degree of crystallinity and metal ion components) suggested that the lower the ratio of drug to silicate, the faster is the amorphization during jar grinding (from 10 days in the ratio 1:0.1 to 5 days in the ratio 1:5). Higher processing humidity (75% RH) decreased the amorphization by 3 times over processing at 0% RH. The mechanisms of interaction of indomethacin co-ground with Neusilin US2 and its subsequent physical stabilization were hydrogen bonding to silanols and surface interaction between metal ions of Neusilin US2 and indomethacin shown by infrared spectral analysis. Indomethacin amorphized by co-grinding with different pharmaceutical silicates (in the ratio 1:5 w/w) was physically stable for at least 3–6 months at 40°C/75% RH. The amount of indomethacin amorphized per gram of silicate was higher than that would be expected for monolayer coverage on the silicate suggesting stabilization of indomethacin in the mesopores of the silicates. Dynamic vapor sorption and porosimetry of co-ground samples also suggested stabilization of amorphous indomethacin in the mesopores of Neusilin US2. ^ The dissolution of co-ground amorphous indomethacin (co-ground with Neusilin US2) in water and phosphate buffer (pH 6.8) changed the pH of the medium leading to complicating variations in the ionization of indomethacin. Further the presence of other polymorphs was detected in the dissolution medium. Using 0.1N HCl (as a dissolution medium), neither a change in the pH of the medium nor any polymorphic transformation was observed. However, we found that increased amounts of amorphous indomethacin (prepared by co-grinding with Neusilin US2 in the ratio 1:5 w/w) added to the dissolution medium also increased peak concentrations by 109 times and plateau concentrations by 13 times that of crystalline indomethacin. The dissolved plateau concentration of indomethacin was found to be stable to recrystallization in this apparently supersaturated state. A solution state interaction between silicic acid, Mg2+ and Al3+ released from Neusilin US2 and indomethacin was determined to be the mechanism behind the higher apparent solubility of co-ground amorphous indomethacin. Thus an enhancement in solubility is NOT solely due to amorphization or partial amorphization as previously reported. This study showed that data on solubility enhancement by co-grinding of drugs with silicates should be interpreted carefully. ^ Indomethacin co-ground (in the drug to silicate ratio of 1:5 w/w) with other silicates (Florite-F, Kaolin, Veegum-F and Aerosil-200) also showed an enhancement in the peak (36 to 97 times) and plateau concentrations (17 to 21 times) of indomethacin as compared to the solubility of crystalline indomethacin. Further enhancement in the solubility (2.3 to 5.6 times) upon storage (as compared to their initial plateau concentrations) of indomethacin amorphized by co-grinding with Neusilin US2, Florite-F, Veegum-F and kaolin at 3 months at 40°C/75% RH was observed. An increase in the dissolved silicic acid (released from Neusilin US2) may account for the increased plateau concentration of indomethacin upon storage. However, the reaction that produces the increase in silicic acid upon storage is not understood. Four structurally diverse drugs (ketoprofen, indomethacin, naproxen and progesterone) amorphized by co-grinding with Neusilin US2 (in a drug to silicate ratio of 1:5 w/w) were physically stable for at least 3 months of storage at 40°C/75% RH. A drug-dependent enhancement in the dissolution/solubility (as compared to that of their respective crystalline counterparts) for all four co-ground amorphous drugs was observed. Thus co-grinding with silicates seems to be a useful strategy to physically stabilize amorphous drugs. ^