Decomposition and Stabilization of the Tablet Excipient Calcium Hydrogenphosphate Dihydrate

Abstract

Calcium hydrogenphosphate dihydrate is a commonly used filler in solid dosage forms. In the literature it is noticed that drug decomposition reactions can be accelerated by the decomposition of CaHPO4.2H2O. The present study has been performed to evaluate various types of this commercially available excipient and to elucidate the impact of selected factors on stability.The influence of both temperature (40, 50 and 60°C) and environmental humidity (26, 34 and 46 % rel. humidity) on the dehydration of calcium hydrogenphosphate dihydrate was studied for a period of two to three months. Five batches of CaHPO4.2H2O were used with different contents of magnesium hydrogenphosphate and sodium pyrophosphate, which are often added to stabilize CaHPO4.2H2O in preparations like aqueous dentifrices. Disks of CaHPO4.2H2O have been prepared in such a way, that the structure of the disks allowed discrimination between the batches in dehydration kinetics. A relatively low velocity of dehydration was found for the batches containing high levels of sodium pyrophosphate. The effect of environmental humidity on the dehydration velocity appeared not to be straightforward: only at 60 °C an acceleration of the dehydration rate was found for all batches due to the increase of relative humidity. The residues after dehydration were analysed by Diffuse Reflectance Infrared Fourier Transform Spectroscopy (DRIFT), Thermogravimetric Analysis and Differential Scanning Calorimetry.The results demonstrate that, independent of the storage condition and the type of calcium hydrogenphosphate dihydrate used, the main decomposition product is anhydrous calcium hydrogenphosphate. This contrasts with interpretations in the literature, which include the formation of decomposition products like hydroxyapatite and phosphoric acid.Although no experiments were performed in the presence of drugs, a hypothesis is proposed on the basis of this study for the mechanism of possible drug decomposition in the presence of calcium hydrogenphosphate dihydrate. The mechanism can be simplified to dissolution of drug in accumulated free water due to dehydration within the drug/excipient system with, possibly, interactions between the drug and calcium hydrogenphosphate dihydrate. Obviously, time, temperature and amount of accumulated free water are important factors in determining the amount of drug decomposed. Accumulation of free water in granulates and tablets containing calcium hydrogenphosphate dihydrate should therefore be avoided or at least limited. This will have implications for e.g. the selection of the quality of calcium hydrogenphosphate dihydrate to be used and for the manufacturing practice of solid dosage forms containing this filler excipient.