Crystalline drugs amorphous content

An exothermic transition can sometimes be observed by DSC on crystallization of the amorphous form. This can be used to quantify the amorphous content of crystalline drugs. A calibration curve that consists of a plot of the enthalpy of crystallization as a function of crystalline content was used to determine if the lyophilized MK-0591 drug substance was... 

Solid state property differences derived from the existence of alternate crystal forms can lead to extensive differences of pharmaceutical importance, e.g., solubility, dissolution rate, and stability. It is claimed that most drug substances show polymorphism (Borka, 1991). As discussed previously, it is essential to determine which of the various forms should be used in a drug product to assure stable and reproducible formulation. A marked difference between the photostability of various crystal modifications of drug substances has been reported. This can be ascribed to differences in inter- and intramolecular binding, differences in diffusability (crystalline vs. amorphous structure), and differences in water content (crystal water, adsorbed water) (Hiittenrauch et al., 1986). 

Microcalorimetry is an extremely sensitive technique that determines the heat emitted or adsorbed by a sample in a variety of processes. Microcalorimetry can be used to characterize pharmaceutical solids to obtain heats of solution, heats of crystallization, heats of reaction, heats of dilution, and heats of adsorption. Isothermal microcalorimetry has been used to investigate drug-excipient compatibility [82]. Pikal and co-workers have used isothermal microcalorimetry to investigate the enthalpy of relaxation in amorphous material [83]. Isothermal microcalorimetry is useful in determining even small amounts of amorphous content in a sample [84]. Solution calorimetry has also been used to quantitate the crystallinity of a sample [85]. Other aspects of isothermal microcalorimetry may be obtained from a review by Buckton [86]. 

Near infrared has been used to quantify amorphous content in a crystalline matrix [64], mixtures of multiple polymorphic forms [65], and physical mixtures of crystalline and amorphous drug in the presence of excipients [66,67]. Otsuka et al. [68] found that Fourier transform (FT)-NIR outperformed x-ray powder diffraction (XRPD) with respect to accuracy statistics over the calibration range and down to 1% (w/w). Other quantitative studies have reported prediction errors of 5 to 6% (w/w) of y-IMC (indomethacin) in a sample matrix including amorphous and a-IMC [69]. These results demonstrate NIR selectivity of the solid-state forms of IMC. Selectivity, the proportion of analyte signal unaffected by other spectral interferences, is especially critical for monitoring dispersions where physical instability could manifest in a combination of amorphous and crystalline forms (including various polymorphs). Similar studies were performed for lactose and showed the possibility to quantify down to 0.5% of crystalline material in an amorphous base [70]. 

Hancock BC, Zografi G (1994) The relationship between the glass transition temperature and the water content of amorphous pharmaceutical sohds. Pharm Res 11(4) 471 77 Hancock BC, Carlson GT, Ladipo DD, Langdon BA, Mullamey MP (2002) Comparison of the mechanical properties of the crystalline and amorphous forms of a drug substance. Int J Phtum 241 73-85... 

In some cases, where a drug substance is highly insoluble, associated amorphous material may be reasonably morphologically stable. In these cases it may be advantageous to include some associated amorphous material to enhance the bioavailability of the product. For both hydrophobic and hydrophilic materials, the amorphous component associated with a crystalline substance can have a profound effect on the overall performance of the product. Extreme care should be taken to understand and quantify the amorphous material. Reduction of amorphous material in poorly soluble/hydrophobic materials may drastically reduce bioavailability. An increase in amorphous content in a hydrophilic material may cause reduction in chemical stability and transformation to an inappropriate form. 

As a final check on the accuracy of the statistical model, the observed results for total related substances and peak B obtained during stability testing of 18 different manufacturing and lab scale batches of drug substance were compared to predicted increases (Figs. 11 and 12). The stability studies represented amorphous and crystalline material with water content ranging from 3-8%. Temperatures used for stability studies were 5°C, 25°C, and 35°C. The duration of the studies was from 11 weeks to 10 months. The... 

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