Physical Stability of Drug Substances

Berglund, M., Bystroem, K., and Persson, B. Screening chemical and physical stability of drug substances./. Pharm. Biomed. Anal. 8 639-643, 1990. 

Impact of Solid-State Characteristics to the Physical Stability of Drug Substance and Drug Product... 

NMR and infrared (IR) spectroscopy are also used to investigate the chemical stability of drug substances. Determination of the hydrolysis rate of esters such as atropine by NMR,647 a nondestructive near-IR analysis of aspirin tablets,648 and determination of the hydrolysis rate of diltiazem by polarimetry649 have been reported. Unusual methods, such as measurement of the dielectric properties of dosage forms like gelatin and methylcellulose microcapsules (Fig. 160), have been used to detect physical changes.650-651 These changes... 

Solid-state physical change of drug substances is one of the major concerns of pharmaceutical stability due to its potential effects on the drug dissolution rate and bioavailability. Closely related to the mechanism of solid-state chemical reactions [44, 45], the physical changes of crystalline dmg substances may include four steps as described in Fig. 12.4. 

Chapter 12 provides a review of solid state characteristics. It discusses the major physical attributes and their impact on the stability of drug substances and drug products. 

Polymorphism is critically important in the design of new drug API [9] and affects a number of areas. The main impact is to the bioavailability and release profile of a drug substance into the body. This is due to differences in solubility and dissolution rate, between the polymorphs. The chemical and physical stability of the formulated drug substance is also dependent on the polymorphic form. Patented registration of all discovered forms and their manufacturing conditions is an important element in protecting a pharmaceutical companies intellectual property. 

There are some useful methods to improve the physical stability of a suspension, such as decreasing the salt concentration, addition of additives to regulate the osmolarity, as well as changes in excipient concentrations, unit operations in the process, origin and synthesis of the drug substance, polymorphic behavior of the drug substance crystals, and other particle characteristics. However, methods based on changes of the particle properties and the surfactants used are the most successful [43],... 

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