Excipient crystalline

Excipient Crystalline maltose Manufacturer SPI Pharma Group Lot No. 8K110947 Magnification lOOx... 

Izutsu K-I, Kojima S. Excipient crystallinity and its protein-structure-stabilizing effect during freeze-drying. / Pharm Pharmacol 2002 54 1033-1039. 

When the excipient matrix in a formulation is largely amorphous, similar XRPD methods can be used to determine the amount of crystalline drug substance present in a drug product. The principles were established in a study that included a number of solid dose forms [40],... 

A, which is shown in the second spectrum from the bottom in Fig. 10.24. Comparing the carbon spectrum of Form A to that of a different crystalline form, Form B, shown in the topmost spectrum of Fig. 10.24, reveals several notable differences in both chemical shifts and line shapes. This, in fact, is often the case for different polymorphs of the same chemical entity, and it enables a clear distinction between the various crystalline forms when present in a mixture. A 13C CPMAS spectrum of a standard sample of the excipients, in the appropriate proportions for the formulation, was also acquired for reference. This is shown as the second spectrum from the top in Fig. 10.24. 

In this example, extensive use of the available reference samples greatly simplified an otherwise highly complex sample mixture. In addition, utilization of a high-field, wide-bore magnet afforded the necessary spectral resolution to easily resolve the two crystalline forms from each other, as well as from the excipients. A lower field magnet, or a less optimized system, may not have been able to differentiate the two forms, and this significant potential impact on the drug s overall bioavailability may have been overlooked. 

Pharmaceutical solids can generally be described as crystalline or amorphous (or glassy). In fact, the actual solid phase composition of a pharmaceutical formulation is usually characterized by an intermediate composition, both crystalline and amorphous in character. In a multicomponent system, such as a solid formulation comprising drug and excipient(s), certain components or even a single component may be... 

The therapy of a chronic disease requires repeated drug dosing. In the case of a short biological half-life, the drug has to be administered up to several times daily within short intervals. To reduce the application frequency, sustained formulations have been developed. For this purpose liquid crystalline excipients are appropriate candidates, because in a liquid crystalline vehicle the drug diffusion is reduced by a factor of 10 to 1000 in comparison with a liquid vehicle such as a solution [35-37]. The factor depends on liquid crystal. 

Crowley and Martini [48] reported on several studies evaluating the impact of unit process operations on hydrates. AU showed some level of dehydration liberating freed crystalline water to participate in moisture-mediated reactions. The authors speculated that such energetic processing conditions are likely to have a similar affect on hydrated excipients with a potential deleterious effect on moismre-sensitive APIs. They commented that classical excipient compatibility studies were ill-equipped to predict such moismre-mediated interactions and that compression, attrition and other energy-intensive unit operations were rarely mentioned as requiring investigations. 

It is essential to understand how and when the polymorphs of drug substance in oral liquid dosage forms and suspensions can be controlled. One approach to study this phenomenon is to seed the formulation with a small amount of a known polymorphic crystal (other than what is used for the product), which is a common practice to rapidly determine what effect this may have on long-term storage. From these types of studies, the appropriate excipients can be used to preserve the specific polymorphic form desired. However, even when the drug in its crystalline form is studied extensively, there are cases when a previously unknown polymorph may be formed in solution and lead to precipitation (14). 

With the aid of X-ray diffraction, it was observed that the formation of amorphous dispersion, instead of crystalline dispersion of drug, in the drug-excipient solid solution contributed to quicker dissolution and a higher amount of total drug release in the dissolution test. Furosemide (Fig. 2) was shown to form amorphous dispersions in the solid solution with either polyvinylpyrrolidone (PVP) or crospovidone, as evidenced by X-ray diffraction (26,27). The extent of amorphous dispersions... 

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. 

Given the complexity that arises from the multitude of interacting variables associated with DPI systems, there are very few excipients that have been incorporated into DPI formulations. Examples of commonly marketed products are listed in Table 2. Lactose has many benefits including a well-established safety profile, low cost, and wide availability. Physicochemical properties of lactose are also relatively desirable from a DPI formulation standpoint smooth surfaces, crystalline, and moderate flow properties. However, lactose may not be suitable for some active... 

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