Drug substance amorphous form

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. 

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. 

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],... 

Crystalline or amorphous forms of fhe drug substance can affect product efficacy. Polymorphic forms usually exhibif different physical-chemical properties, including melting point and solubility. The occurrence of polymorphic forms with drugs is relatively... 

Hancock BC, Carlson GT, Ladipo DD, Langdon BA, Mullarney MP. Comparison of the mechanical properties of the crystalline and amorphous forms of a drug substance. Int J Pharma 2002 241 73-85... 

Q Alteration of the Solid State of the Drug Substances Polymorphs, Solvates, and Amorphous Forms... 

Some excipients contain a certain amount of amorphous form such as spray-dried lactose,27 and others are hygroscopic, such as microcrystalline cellulose.28 These excipients will adsorb water, which causes a change in the micro-environment of the formulation. If the drug substance is moisture-sensitive, degradation may occur quickly. Therefore, consider both drug-excipient compatibility and excipient impurity profile in selecting excipients for low-dose drug products. 

FIGURE 7 Characterization of amorphous form, (a) DSC thermogram of amorphous substance. Thermogram is characterized by a glass transition temperature (Tg) above which the amorphous form is mobile and recrystallizes (Tcrys) into a crystalline form which finally melts (7m). (b) Amorphous form that does not show any peaks in XRD as it does not have regular arrangement of molecules. Shallow peaks are indicative of an amorphous drug substance. 

Exothermic Crystallization Precipitation Solidification Adsorption Solvent vapor induced crystallization of amorphous excipients Formation of salt forms of drug substances Melt granulation with semisolid excipients Solvent vapor sorption by drug substances... 

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... 

Many drug substances appear in more than one polymorphic form. The form is determined by certain conditions during the crystallization step. Occasionally drug substances are precipitated in such a way that molecules do not organize themselves in any set pattern, resulting in an amorphous powder. It is also possible for solids to entrap solvents stoichiometrically to form solvates. 

If possible, ethanol is used as the solvent. Unfortunately, its solvent power is inadequate for a number of active substances. However, as the active substance must be completely dissolved to distribute the drug in the carrier in a very fine crystalline to amorphous form, it is then necessary to resort to the use of another organic solvent such as chloroform. 

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