Effect of pharmaceutical processing on the solid-state Maillard reaction between metoclopramide hydrochloride and lactose

Zhihui Qiu, Purdue University

Abstract

The primary goal of this research was to determine the role of milling and compression on the facilitation of the Maillard reaction and provide information about solid-state chemical stability of metoclopramide hydrochloride (an amine) in the presence of lactose, a reducing sugar. This project also seek to test the hypothesis that the amorphous phase, which is expected to form during processing, significantly enhance the reactivity of the crystalline form toward the Maillard reaction. The influence of moisture, temperature, and different lactose and metoclopramide hydrochloride forms on the reactivity of the solid-state Maillard reaction was examined. Higher reaction rates were observed for solid forms that were physically less stable for both metoclopramide hydrochloride and lactose. The effects of surface area and vapor-phase diffusion were also investigated. It can be concluded that these factors were all critical in determining the reaction rate of the solid-state Maillard reaction, although the influence of each factor varied at different conditions. For example, the surface area of metoclopramide hydrochloride is a rate-controlling factor for the anhydrate form at 105°C and 0% RE, but not for the monohydrate form at 60°C and 64% RH, because the molecular mobility of the monohydrate form was very low, and had a dominating effect on the reaction rate comparing to the effect of surface area. Pharmaceutical processing, such as milling and compression, tends to introduce disorder in the form of defects or amorphous regions into crystalline solids and create new contact areas between the drugs and excipients. Milling was found to increase the reactivity of anhydrous metoclopromide hydrochloride by increasing the contact area and the formation of defect and amorphous regions. Higher reaction rates were observed in tablets than in powder mixtures of metoclopramide hydrochloride anhydrate and three forms of lactose (spray-dried lactose anhydrate, spray-dried lactose monohydrate, and amorphous lactose). For tablets composed of metoclopramide hydrochloride anhydrate and amorphous lactose, a linear relationship between reaction rate and compression force was observed. This may be due to the increased contact between the drug and lactose and retarded water vapor diffusion from the tablets. The characteristics of solid-state kinetics were discussed. A second order kinetic model was used to fit the degradation data of colyophilized metoclopromide hydrochloride and lactose. The activation energy was calculated as 52.5 kcal/mol.

Degree

Ph.D.

Advisors

Byrn, Purdue University.

Subject Area

Pharmacology|Pharmaceuticals

COinS