Crystallization precipitation inhibition

With preformed ACP at ratios of only one PL molecule per 30-50 Ca atoms, phosphatidyl serine markedly delays HA crystal formation. When phosphatidyl serine is present during ACP precipitation, inhibition of conversion to HA is less pronounced, but crystal habit and aggregation are greatly altered resulting in stacks of thin, membrane-like sheets approximately 3—42 A thick. Phosphatidyl serine... 

Osteocalcin has two high affinity and two or three low affinity sites for calcium. It limits growth of calcium phosphate crystals, and inhibits precipitation of hydroxyapatite. This cannot be achieved by the decarboxylated protein. Calcified tissue from various sources also contains gla proteins.459 Gla proteins are not found in invertebrates. 

The development of bisphosphonates for clinical purposes began with the discovery that inorganic pyrophosphate is present in blood and urine and inhibits the precipitation of calcium and phosphate (1). Derivatives of pyrophosphate had been widely used for industrial purposes, because they inhibit the precipitation of calcium carbonate. Their principal use was as antiscaling additives in washing powders, water, and oil brines, to prevent deposition of calcium carbonate scale. It was then found that pyrophosphate binds strongly to calcium phosphate, prevents both the formation and dissolution of calcium phosphate crystals, and inhibits calcification in vitro. The bisphosphonates are used to treat bone diseases characterized by increased osteoclastic bone resorption (2). Long-term administration of low doses of oral bisphosphonates is considered to be valuable in patients with postmenopausal osteoporosis (3,4). 

As Fig. 9.10 shows, the microcentrifuge test is also used (1) to quantify precipitation inhibition for compounds that rapidly crystallize and (2) to compare dissolution rates for SDDs of more lipophilic compounds, which tend to dissolve more slowly as particle size increases during process scale-up. A simulated gastric exposure step before dissolution in simulated intestinal media can also be added. This option is useful when evaluating weakly basic compounds that have pH-dependent solubility (Mathias et al. 2013). 

Since transport across the biological membrane of weak bases will be more pronounced in the small intestine (uptake of the unionized form), sufficient precipitation inhibition (polymer) is required upon transfer of the supersaturated solution to the intestine. Therefore, one cannot rely on dissolution studies at constant acidic pH to predict the performance of formulations of weak bases in vivo (Miller et al. 2007). For instance. Six et al. (2005) observed a discrepancy between the results of in vitro dissolution tests in acidic medium and in vivo absorption for four solid dispersions of ITR faster release and increased supersaturation in acidic medium correlated with lower bioavailability. Presumably, this effect can be explained by differences in crystallization rate upon transfer to the small intestine (increased driving force for precipitation in case of higher supersaturation). Thus, it is crucial to simulate the GI pH shift during supersaturation dissolution testing of weak bases to evaluate whether supersaturation is maintained in the small intestine. 

Ghelants and Precipitation Inhibitors vs Dispersants. Dispersants can inhibit crystal growth, but chelants, such as ethylenediaminetetraacetic acid [60-00-4] (EDTA), and pure precipitation inhibitors such as nitrilotris(methylene)tris-phosphonic acid [6419-19-8], commonly known as amino trismethylene phosphonic acid (ATMP), can be more effective under certain circumstances. Chelants can prevent scale by forming stoichiometric ring stmctures with polyvalent cations (such as calcium) to prevent interaction with anions (such as carbonate). Chelants interact... 

Sodium carboxymethyl chitin and phosphoryl chitin had most evident influences on the crystallization of calcium phosphate from supersaturated solutions. They potently inhibited the growth of hydroxyapatite and retarded the rate of spontaneous calcium phosphate precipitation. These chitin derivatives were incorporated into the precipitate and influenced both the phase and morphology of the calcium phosphate formed (flaky precipitate resembling octacalcium phosphate instead of spherical clusters in the absence of polysaccharide) [175]. 

Calcium oxalate (723) occurs as the monohydrate (whewellite, the thermodynamically stable form under ambient conditions (724)), the dihydrate (weddellite) in plant calcium stores and in sap, or the trihydrate (725). Calcium oxalate also plays a structural role in plants. Oxalate, for example from excessive amounts of rhubarb or spinach, inhibits absorption of Ca2+ from the GIT precipitation of calcium oxalate is the reason for the toxicity of oxalates. Calcium oxalate may also occur in man, where it can appear as minute star-shaped crystals in the urine. It is the main constituent of the majority of urinary calculi in man (726,727). The relationships between dietary calcium... 

Calcium phosphate precipitation may also be involved in the fixation of phosphate fertilizer in soils. Studies of the uptake of phosphate on calcium carbonate surfaces at low phosphate concentrations typical of those in soils, reveal that the threshold concentration for the precipitation of the calcium phosphate phases from solution is considerably increased in the pH range 8.5 -9.0 (3). It was concluded that the presence of carbonate ion from the calcite inhibits the nucleation of calcium phosphate phases under these conditions. A recent study of the seeded crystal growth of calcite from metastable supersaturated solutions of calcium carbonate, has shown that the presence of orthophosphate ion at a concentration as low as 10-6 mol L" and a pH of 8.5 has a remarkable inhibiting influence on the rate of crystallization (4). A seeded growth study of the influence of carbonate on hydroxyapatite crystallization has also shown an appreciable inhibiting influence of carbonate ion.(5). 

It is effective for treatment of acute attacks of gout. It has no effect on renal excretion of uric acid. It binds to tubulin, it interferes with function of mitotic spindles, causes depolymerization and disappearance of fibrillar microtubules in granulocytes. In gout, the useful of colchicine is due to the inhibition of the release of glycoproteins from granulocytes in inflamed joint thus preventing precipitation of uric acid crystals and release of lysosomal enzymes. 

The precipitation of calcium phosphate in the development of bone structure is a major topic beyond the scope of this discussion. It should be noted, however, that this process can be controlled by proteins and/or polysaccharides that provide sites for nucleation and that match features in the geometry of the crystal, such as repeat distances between certain groups. Other proteins can inhibit crystal development. Granular deposits of calcium involve small crystals so that deposition and reabsorption will be rapid. The size of the crystals can be controlled by their protein and/or polysaccharide environment, or even by a vesicular membrane which could act as a template. 

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