Precipitation kinetics calcium phosphates

Despite the importance of the precipitation of calcium phosphates, there is still considerable uncertainty as to the nature of the phases formed in the early stages of the precipitation reactions under differing conditions of supersaturation, pH, and temperature. Although thermodynamic considerations yield the driving force for the precipitation, the course of the reaction is frequently mediated by kinetic factors. Whether dicalcium phosphate dihydrate (CaHPO HoO, DCPD), octacalcium phosphate (Ca HfPO, 2.5 H20, OCP), hydroxyapatite (Cag (PO fOH), HAP), amorphous calcium phosphate (ACP), or a defect apatite form from aqueous solution depends both upon the driving force for the precipitation and upon the initiating surface phase. Thermodynamically, the relative supersaturation, o, is given by... 

Numerous kinetic studies have been made of the spontaneous precipitation of calcium phosphates from solutions containing concentrations of lattice ions considerably in excess of the solubility values (33, 34). Although attempts, are usually made to control the mixing of reagent solutions, it is difficult to obtain reproducible results from such experiments since chance nucleation of solid phases may take place on foreign particles in the solution. Many of these difficulties can be avoided by studying the crystal growth of well-characterized seed crystals in metastable supersaturated solutions of calcium phos.phate. 

Calcium sulfate crystals were precipitated in a Continuous Mixed Suspension Mixed Product Removal (CMSMPR) crystallizer by mixing of calcium phosphate and sulfuric acid feed streams. The formed calcium sulfate hydrate (anhydrite, hemihydrate and dihydrate) mainly depends on the temperature and the solution composition. The uptake of cadmium and phosphate ions in these hydrates has been studied as a function of residence time and solution composition. In anhydrite, also the incorporation of other metal ions has been investigated. The uptake was found to be a function of both thermodynamics and kinetics. 

Hydroxyapatite (with some carbonate inclusions) is the most stable of the possible calcium phosphate salts that can be formed under physiological conditions. However, it is not the most rapid one to form. Instead, octacalcium phosphate (OCP) will precipitate more readily than hydroxyapatite. This led Brown in 1987 to propose that, as the kinetically favoured compound, OCP precipitates first, and then undergoes irreversible hydrolysis to a transition product OCP hydrolyzate [68]. This hypothesis is consistent with the observation that enamel comprises hydroxyapatite crystals that have the long, plate-like morphology that is generally considered characteristic of OCP crystals [69]. Overall, it seems that enamel crystals, with their elongated form, result from early precipitation of OCP, which forms a template on which hydroxyapatite units grow epitaxially [70,71]. This leads to enamel mineralisation with the observed thin, ribbon-like structure of crystals. 

In this paper we discuss the chemistry of aqueous calcium phosphate systems from the point of view of both equilibriiam and kinetic considerations. It will be shown that the chemical composition of the calcium phosphate precipitated under any given set of conditions, may be determined kinetically rather than simply on the basis of thermodynamic driving forces. 

Measurements of the specific surface area, SSA, of the products grown at various times indicate that the initial formation of a microcrystalline or amorphous precursor leads to a rapid increase in SSA. The development of these phases is also observed by scanning electron microscopy, and dissolution kinetic studies of the grown material have indicated the formation of OCP as a precursor phase ( , 7). The overall precipitation reaction appears to involve, therefore, not only the formation of different calcium phosphate phases, but also the concomitant dissolution of the thermodynamically unstable OCP formed rapidly in the initial stages of the reaction. In the presence of magnesium ion the overall rate of crystallization is reduced and lower Ca P ratios are observed for the first formed phases (51). 

However, the use of buffers in parenterals is not always benign, and numerous instances have been summarized where buffers or other excipients have caused stability problems.For instance, the com-plexation of Ca(II) and Al(III) with phosphate buffer solutions has been studied at great length, as well as the kinetic characteristics of the subsequent precipitation of calcium and aluminum phosphate salts. The use of metal complexing excipients, such as citric... 

Fig. 6-16. Idealized scheme for calcium phosphate precipitation kinetics.

A number of laboratory studies have been recorded recently aimed at characterizing the kinetics of both the chemical reaction and crystallization steps in a reaction crystallization process. Examples of liquid phase reactions studied for this purpose are the crystallization of salicylic acid from aqueous solutions of sodium salicylate using dilute sulphuric acid (Franck et al, 1988) and the crystallization of various calcium phosphates by reacting equimolar aqueous solutions of calcium nitrate and potassium phosphate (Tsuge, Yoshizawa and Tsuzuki, 1996). Several aspects of crystal size distribution control in semi-batch reaction crystallization have been considered by Aslund and Rasmuson (1990) who studied the crystallization of benzoic acid by reacting aqueous solutions of sodium benzoate with HCl. An example of crystallization arising from a gas-liquid reaction in an aqueous medium is the precipitation of calcium carbonate from the reaction between calcium hydroxide and CO2 (Wachi and Jones, 1995). 

Calcium phosphate precipitation has been described as a fairly compHcated process, and is known to depend on several parameters, such as the calcium and phosphate ion concentrations, pH and temperature [25]. Although the thermodynamics and kinetics of HA precipitation have been reported, there is no clear correlation between precipitation conditions, the driving force for precipitation, and the morphology of the HA powders synthesized from these reactions. When Kumar et al. analyzed the changes in HA morphology in relation to the reaction temperature, they found that needle-shaped particles with a high aspect ratio were formed at 40 °C, but that spheroidal particles formed when the precipitation temperature was increased to 100 °C [26]. 

---