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Although proteins are often frozen during processing or freeze-dried after formulation to improve their stability, they can undergo degradation leading to losses in biological activity during the process. During freezing, the physical environment of a protein changes dramatically leading to the development of stresses that impact protein stability. Low temperature, freeze-concentration, and ice formation are the three chief stresses resulting during cooling and freezing. Because of the increase in solute concentrations, freeze-concentration could also facilitate second order reactions, crystallization of buffer or non-buffer components, phase separation, and redistribution of solutes. An understanding of these stresses is critical to the determination of when during freezing a protein suffers degradation and therefore important in the design of stabilizer systems. With the exception of a few studies, the relative contribution of various stresses to the instability of frozen proteins has not been addressed in the freeze-drying literature. The purpose of this review is to describe the various stages of freezing and examine the consequences of the various stresses developing during freezing on protein stability and to assess their relative contribution to the destabilization process. The ongoing debate on thermodynamic versus kinetic mechanisms of stabilization in frozen environments and the current state of knowledge concerning those mechanisms are also reviewed in this publication. An understanding of the relative contributions of freezing stresses coupled with the knowledge of cryoprotection mechanisms is central to the development of more rational formulation and process design of stable lyophilized proteins.

It has been demonstrated that the theoretical approach does provide an accurate estimate of the maximum solubility enhancement by an amorphous drug relative to its crystalline form for structurally diverse insoluble drugs when recrystallization during dissolution is minimal.

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The amount of calcium available for absorption is dependent, in part, on its sustained solubility in the gastrointestinal (GI) tract. Many calcium salts, which are the calcium sources in supplements and food, have pH-dependent solubility and may have limited availability in the small intestine, the major site of absorption. The equilibrium solubility of four calcium salts (calcium oxalate hydrate, calcium citrate tetrahydrate, calcium phosphate, calcium glycerophosphate) were determined at controlled pH values (7.5, 6.0, 4.5 and < or = 3.0) and in distilled water. The solubility of calcium carbonate was also measured at pH 7.5, 6.0 and 4.5 with two CO(2) environments (0.3 and 152 mmHg) above the solution. The precipitation profile of CaCO(3) was calculated using in-vivo data for bicarbonate and pH from literature and equilibrium calculations. As pH increased, the solubility of each calcium salt increased. However, in distilled water each salt produced a different pH, affecting its solubility value. Although calcium citrate does have a higher solubility than CaCO(3) in water, there is little difference when the pH is controlled at pH 7.5. The partial pressure of CO(2) also played a role in calcium carbonate solubility, depressing the solubility at pH 7.5. The calculations of soluble calcium resulted in profiles of available calcium, which agreed with previously published in-vivo data on absorbed calcium. The experimental data illustrate the impact of pH and CO(2) on the solubility of many calcium salts in the presence of bicarbonate secretions in the intestine. Calculated profiles using in-vivo calcium and bicarbonate concentrations demonstrate that large calcium doses may not further increase intestinal calcium absorption once the calcium carbonate solubility product has been reached.

The processing humidity and the ratio of indomethacin to Neusilin US2 are important factors to be considered to affect amorphization during ball milling. Amorphous indomethacin can be stabilized by co-grinding with Neusilin US2.