Amorphous drug powder

K below Tg, an amorphous drug powder formed compacts that were significantly more brittle than those formed from the crystalline form of the drug although the tensile strengths of the compacts were similar. 

Nalidixic acid is another example of BCS class II drug, with oral bioavailability limited by poor solubility and slow dissolution (40). Compared to drug powder alone, the solid dispersion of nalidixic acid with P-cyclodextrin or PYP or sodium starch glycolate had much faster dissolution. X-ray diffraction studies revealed the formation of amorphous areas and less degree of crystallinity in the solid dispersion of nalidixic acid with excipients. 

Resultant particles have a high glass transition temperature, which aids in stabilizing the amorphous state. These particles can be compressed into tablets. In one case, tablets containing 150 mg drug were pressed from a 1 1 mixture of the processed drug powder, microcrystalline cellulose and 5% carboxymethylcellulose. 

The physical properties of the solid state seen in crystals and powders of both drugs and pharmaceutical excipients are of interest because they can affect both the production of dosage forms and the performance of the finished product. Powders, as Pilpel reminded us, can float like a gas or flow like a liquid but when compressed can support a weight. Fine powders dispersed as suspensions in liquids are used in injections and aerosol formulations. Both liquid and dry powder aerosols are available and are discussed in Chapter 9 some properties of compacted solids are dealt with in Chapter 6. In this chapter we deal with the form and particle size of crystalline and amorphous drugs and the effect these characteristics have on drug behaviour, especially on drug dissolution and bioavailability. 

An amorphous drug substance is a powdered material without crystalline structure. Thus, no X-ray powder diffraction pattern or thermal peaks in the DSC can be observed. Amorphous powder can be prepared by rapid cooling of a solution, coprecipitation with an organic solvent, or freeze-drying or from the melt. Because the entropy of the amorphous powder is high, the solubility... 

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]. 

Weuts 1, Van Dycke F, Vootspoels J, De Cort S, Stokbroekx S, Leemans R et til (2011) Physicochemical properties of the amorphous drug, cast films, and spray dried powders to predict formulation probability of success for sohd dispersions etravirine. J Pharm Sci 100 260-274... 

Both densification and compaction, being energy intensive processes, are sensitive to the physico-mechanical properties of the powders, more so in case of amorphous form. Bruno and colleagues showed that the dynamic indentation hardness of compacts of amorphous drug particles was approximately 30 % higher than that of... 

Ivanisevic I, Bates S, Chen P (2009) Novel methods for the assessment of miscibility of amorphous drug-polymer dispersions. J Pharm Sci 98 3373-3386 Ivanisevic I, McClurg RB, Schields PJ, Gad SC (2010) Uses of X-ray powder diffraction in the pharmaceutical industry drug discovery, development, and manufacturing, pharmaceutical sciences... 

Investigations for the occurrence of polymorphism have been undertaken by ir spectroscopy, differential scanning calorimetry and x-ray powder diffraction (Guinier-de Wolff). No polymorphism has been observed so far. An amorphous form may be prepared artificially by rapid evaporation of a methanolic solution of the drug substance. 

Amorphous or noncrystalline forms can exist and the energy required for a molecule of drug to escape from a crystal is much greater than that required to escape from an amorphous powder. Therefore, the amorphous form of a compound is always more soluble than a corresponding crystal form. 

Furlanetto et al. (26) attempted to predict and compare the solid-state stability of cefazolin sodium and cephaloridine sterile powders using data obtained at 37°C, 45°C, and 60°C. They analyzed samples for up to 6 months and found cephaloridine to be more stable than cefazolin sodium, in contrast to the relative stability of the compounds as indicated by their respective compendial storage instructions. They attributed greater stability of the cephaloridine samples to greater crystallinity compared to the cefazolin sodium samples which appeared to be mostly amorphous. Rather than comparing different samples of the same drug, this study determined the relative stability of two different drugs and compared the results to expectations based on previous information. 

Most drug and inactive excipients used in tablet formulation are in the solid state as amorphous powder or crystals of various morphological structures. There may be substantial differences in particle size, surface area, crystal morphology, wetting, and flowability as well as many physical properties of drug, excipients, and their blends [16]. Table 12 describes common micromeritic topics important to pharmaceutical preformulation. 

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