Amorphous form stability

The most commonly used polymers for the MBP process are HPMCAS (L, M, and H grades) and polymethacrylate-based polymers, e.g., Eudragit LlOO, LlOO-55, and S100. Other ionic polymers such as cellulose acetate phthalate (CAP), hypromellose phthalate (HP), polyvinyl acetate phthalate (PVAP), and cationic polymer Eudragit El00 can also be used. The polymer use levels are determined based on the drug loading and amorphous form stability. 

Silica sols are often called colloidal silicas, although other amorphous forms also exhibit colloidal properties owing to high surface areas. Sols are stable dispersions of amorphous siUca particles in a Hquid, almost always water. Commercial products contain siUca particles having diameters of about 3—100 nm, specific surface areas of 50—270 m /g, and siUca contents of 15—50 wt %. These contain small (<1 wt%) amounts of stabilizers, most commonly sodium ions. The discrete particles are prevented from aggregating by mutually repulsive negative charges. 

Another physical property that can affect the appearance, bioavailability, and chemical stability of pharmaceuticals is degree of crystallinity. Amorphous materials tend to be more hygroscopic than their crystalline counterparts. Also, there is a substantial body of evidence that indicates that the amorphous forms of drugs are less stable than their crystalline counterparts [62]. It has been reported, for example,... 

Often the stability of a drug in the solid state depends on its physical state (i.e., crystalline or amorphous [8]). If freeze-drying produces an amorphous solid and the amorphous form is not stable, then freeze-drying will not provide an acceptable product. 

This chapter describes some of the properties of solids that affect transport across phases and membranes, with an emphasis on biological membranes. Four aspects are addressed. They include a comparison of crystalline and amorphous forms of the drug, transitions between phases, polymorphism, and hydration. With respect to transport, the major effect of each of these properties is on the apparent solubility, which then affects dissolution and consequently transport. There is often an opposite effect on the stability of the material. Generally, highly crystalline substances are more stable but have lower free energy, solubility, and dissolution characteristics than less crystalline substances. In some situations, this lower solubility and consequent dissolution rate will result in reduced bioavailability. 

Amorphous form provide the most rapid dissolution and the most often increased solubility by supersaturation however, practical usefulness is limited by stability issues, including transformation of the solid state form. 

The results of the polymorph screening step in combination with bioavailability studies, provide the information required by the clinical research team to nominate the desired crystal form of the API for long term manufacture and formulation. This form will usually be the most stable polymorph, where a number of forms have been identified, or a salt form if bioavailability is low or when there are formulation concerns regarding polymorph stability. In some cases it may be necessary to select an amorphous form or metastable polymorph because of crystallization difficulties, time constraints or bioavailability requirement. The nomination of a hydrate or solvate is generally avoided because of their relative instability and compositional variability such constraints are less of a concern for the earlier synthetic intermediates. 

M. J. Pikal, D. R. Rigsbee, The Stability of Insulin in Crystalline and Amorphous Solids Observation of Greater Stability for the Amorphous Form , Pharm. Res. 1997, 14, 1379-1387. 

The stability of a suspension-emulsion of benzimidazole in oil was evaluated by quantifying the fractions of polymorphs A, B, and C as soon as prepared and after one year using a calibration model developed using pure polymorph samples [233]. The concentrations of mannitol in its amorphous form and each of three polymorphs were determined within 5% mass fraction, relative to salmon calcitonin [234]. The powders all were sized for delivery by respiration, less than 5 tan. 

In weathering situations, saturation of fluids with SiC relative to any species of pure silica is probably only rarely achieved. In continental and shallow sea deposits, silica is precipitated in some initially amorphous form, opaline or chert when lithified or extracted by living organisms. Authigenically formed silicates are probably not in equilibrium with quartz when they are formed. As compaction increases in sediments, silica concentrations in solution are again above those of quartz saturation (15 ppm) and again it must be assumed that the diagenetic minerals formed are not in equilibrium with a silica polymorph except where amorphous silica is present. It is possible that burial depths of one or two kilometers are necessary to effectively stabilize that quartz form. It must be anticipated that the minerals formed under conditions of silica saturation near the earth s surface will be a minority of the examples found in natural rock systems. 

Matsuda, Y. and S. Kawaguchi. 1986. Physicochemical characterization of oxyphenbutazone and solid-state stability of its amorphous form under various temperature and humidity condEtlrota. 

An early example of Raman mapping by Breitenbach et al. [52] showed that when crystalline ibuprofen is formulated in a hot melt extrudate the API changes to the amorphous form. Ibuprofen is a sparingly water-soluble compound, so this formulation provides a route to better bioavailability via the more soluble amorphous form. Using confocal Raman mapping the form of the API was determined at the time of manufacture and under stress conditions and was used to assess the stability of the amorphous form. These studies also showed that the API was homogeneously distributed throughout the formulation based on the relative band intensities of the amorphous API and a formulation excipient, polyvinylpyrrolidone (PVP). 

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