Subject polymorphic forms

Various drugs are known to exist in different polymorphic forms (e.g., cortisone and prednisolone). The rate of conversion from a metastable into the stable form is an important criteria to be considered with respect to the shelf life of a pharmaceutical product. Polymorphic changes have also been observed during the manufacture of steroid suspensions. When steroid powders are subjected to dry heat sterilization, subsequent rehydration of anhydrous steroid in the presence of an aqueous vehicle results in the formation of large, needle-like crystals. A similar effect may be... 

US patent 6,767,921, Polymorphic forms of fasidotril, their methods of preparation and pharmaceutical compositions comprising them [115]. The subject of this invention are polymorphic Forms I, II, III, IV of benzyl (S,S)-2-(2-acetylsul-phanylmethyl-3-benzo[l,3]dioxol-5-ylpropionyl-amino)propionate (i.e., fasidotril), their methods of preparation, and novel pharmaceutical compositions containing them. 

Omeprazole is known to exist in at least two well-defined polymorphic forms, which have been the subject of patent documentation. 

The transformation of crystals from the P to the P form takes place in the solids present in a fat. However, the rate of this transformation is greatly influenced by the amount of liquid oil in the fat. A suitable method to estimate the p stability of a fat is temperature cycling. An example is given in Table 9, where palm oil products were subjected to temperature cycling between 4 and 20°C. A cycle may take two or more days. The polymorphic forms can be measured at the end of each cycle. A product such as hydrogenated palm oil or palm olein will show no presence of P polymorphs after four cycles. Palm oil and palm stearin will... 

The solubility of the most stable crystal form in a polymorphic system is termed the equilibrium solubility. While the measurement of equilibrium solubility at a given temperature is a routine practice in pharmaceutical research (Grant and Brittain, 1995), evaluation of the solubility of a metastable polymorph is frequently more complicated owing to the tendency of metastable forms to undergo a phase transformation to the more stable polymorph in the medium of measurement. It is therefore prudent to include a determination of the phase at the completion of any solubility measurement to verify exactly which polymorphic form has been the subject of the measurement. 

Making changes to the filings is possible if proposed changes are submitted in writing and approved before they are implemented. Although small changes to a synthesis are quick to effect, new toxicity or bioavailability studies lag. Approval is not subject to acceleration, so these precautionary studies protect patients from any toxicity of new impurities or from the ineffectiveness of a new polymorphic form that is not bioavailable. 

At any one temperature and pressure, only one crystal (polymorph) form will be stable. Any other polymorph found under these condition is metastable and will eventually convert to the stable form, but the conversion may be very slow (sometime can take years). The metastable form is a higher energy form and usually has a lower melting point, greater solubility, and faster dissolution rate. Examples are chloramphenicol palmitate (Aguir etal. 1967) and sulfameter (Khalil et al. 1972). This sulfanilamide is reported to have six polymorphs. Crystalline form II is about twice as soluble as crystalline form III. Studies in normal subjects showed that the rate and extent of absorption is approximately 40% greater from form II. Table 8.3 provides a few examples of drugs that exhibit polymorphism. 

Going from the polymorphic forms of cellulose back to cellulose I is difficult but can be accomplished by partial hydrolysis. The subject of the polymorphic forms of cellulose has been reviewed (10,11). 

Raman spectroscopy provides molecular information about the crystalline, as well as the amorphous forms of a material. In this method, the material is subjected to a laser beam and a spectrum of the scattered light obtained. The spectrum shows vibrational bands of the material at their characteristic frequencies. The amorphous and polymorphic forms of a material can be distinguished by their characteristic spectra. 

In the metallic actinides, particularly in U, Np, and Pu, the subject of transformations from one polymorphic form to another is a complicated one, because of the unique crystallographic relationships and because of the large number of polymorphic forms that exist in a relatively narrow range of temperature. The transformations and their products have characteristics that depend on temperature, on the rate of change of temperature, on composition, and on initial structure. 

There are four polymorphic forms, a-, )5-, y-, and phase, known for p-nitrophenyl nitronyl nitroxide p-NPNN) [22—25] (Table 15.3). Each of them can be separately prepared by properly adjusting the conditions for depositing crystals [26]. The crystallographic constants of these phases are given in Table 15.3. The orthorhombic jS-phase is the most stable form and the other forms are subject to gradual phase change to the... 

PBT (also referred to as poly(tetramethylene terephthalate)) became the subject of keen interest in the mid-1970s when three groups of researchers [42,43,54] independently reported that it could crystallize in two distinct polymorphic forms. The a-form was found in a relaxed sample, whereas the... 

For materials in which a large proportion of glassiness is formed, DSC can lead to an estimate of the crystalline or amorphous (by subtraction) content provided the heat of fusion of the fully crystalline material is known. The heat of fusion of a sample can be percentified as a function of the heat of fusion of a standard giving the crystalline content. Clearly, the same polymorphic form should be present in both sample and standard. The technique has errors and can not be used to estimate the amorphous content when this is low, perhaps less than 5%. Re-scanning a glassy material may determine if it is subject to polymorphic modifications. 

In this chapter we introduced the concept of shock waves, ignoring the features that distinguish solids from fluids. The properties include shear strength, polymorphic phase transformations, heterogeneous structure, anisotropy, and viscoplastic behavior. These topics make up the majority of the subject of shock compression of solids, and form a large portion of the rest of this book. 

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