Chemical Degradation

The major known chemical degradation pathways for peptides and proteins are deami-dation, racemization, isomerization, hydrolysis, disulfide formation exchange, P-elimina-tion, and oxidation. Asparagine residues in peptides and proteins undergo deamidation via cyclic imide formation followed by subsequent hydrolysis to form the corresponding aspartic and wo-aspartic acid peptides. This mechanism occurs primarily under neutral-to-basic pH conditions. Deamidation of an asparagine residue to the...

Changes in Drug Dissolution from Tablets and Capsules

Dissolution (or release) of a drug substance from a dosage form, such as a tablet or a capsule, is a very important characteristic. Dissolution characteristics have been known to change upon storage. For example, the dissolution rate of carbamazepine tablets decreased markedly when they were stored at room temperature and 100 RH for a period as short as 6 days (Fig. 163).670 Such dramatic changes in dissolution rate may alter the bioavailability of the drug. However, changes in in vitro...

Decarboxylation and Elimination

Drug substances having a carboxylic acid group are sometimes susceptible to decarboxylation, as shown in Scheme 42. 4-Aminosalicylic acid is a good example.168 Foscarnet also undergoes decarboxylation under strongly acidic conditions, 169 whereas etodolac is susceptible to decarboxylation by acid catalysis.170 Other elimination reactions have been reported for various drug substances, as shown in Scheme 43. Trimelamol eliminates its hydroxymethyl groups and forms formaldehyde.171 Levothyroxine...

Adsorption onto and Absorption into Containers and Transfer of Container Components into Pharmaceuticals

Pharmaceuticals may interact with packaging and containers, resulting in the loss of drug substances by adsorption onto and absorption into container components and the incorporation of container components into pharmaceuticals. Diazepam in intravenous fluid containers and administration sets exhibited a loss during storage due to adsorption onto glass and adsorption onto and absorption into plastics.740 741 Nitroglycerin, a liquid with a significant vapor pressure, is also significantly...

Amides

Amide bonds are commonly found in drug molecules. Amide bonds are less susceptible to hydrolysis than ester bonds because the carbonyl carbon of the amide bond is less electrophilic (the carbon-to-nitrogen bond has considerable double bond character) and the leaving group, an amine, is a poorer leaving group (Scheme 10). Figure 3 shows the structure Scheme 9. Other esters of pharmaceutical relevance susceptible to hydrolysis. Scheme 9. Other esters of pharmaceutical relevance susceptible to...

Temperature Dependence of the Degradation Rate of Peptide and Protein Drugs

Pots Syndrome

Stability prediction for peptide and protein drugs under accelerated testing conditions is possible if the temperature dependence of the degradation rate is determined and found to be well behaved. The temperature dependence can often be represented by the Arrhenius equation, as was seen with small-molecule drugs. Linear Arrhenius plots and the values of apparent activation energy calculated from the slopes have been reported for chemical degradation of various peptides in aqueous solutions....

Methods for Detecting Chemical and Physical Degradation

Critical for good studies involving the analysis of drugs and their degradants is the establishment and validation of so-called stability indicating method(s). Various chroma-tographic methods are best used to detect chemical changes with time under a variety of stress or nonstress conditions. Validated chromatographic separation techniques such as high-performance liquid chromatography (HPLC) and gas chromatography (GC) coupled to sophisticated detectors provide not only useful quantitative...

Photodegradation

Photodegradation has been reported for a large number of drug substances. The mechanisms for these reactions are generally very complex. As exemplified by chloro-quine207 and primaquine,208 shown in Schemes 53 and 54, respectively, photodegradation Scheme 53. Photodegradation of chloroquine (R, and R2 are unknown). Scheme 53. Photodegradation of chloroquine (R, and R2 are unknown). Scheme 54. Photodegradation of primaquine. Scheme 54. Photodegradation of primaquine. generally yields numerous...

Factors Affecting Physical Stability

The physical stability of pharmaceuticals is affected by many of the same variables that affect chemical stability. Specifically, the physical stability of solid pharmaceuticals is affected by the plasticizing effect of water, presumably owing to increases in molecular Figure 141. Moisture adsorption of a sucrose-potassiumbromide mixture plotted according to Eq. 3.1 . 25 C . Reproduced from Ref. 602 with permission. Figure 141. Moisture adsorption of a sucrose-potassiumbromide mixture plotted...

Kinetics of Solid Phase Transitions

Detailedmechanismsformost efficacy and safety of drug products have not been extensively studied because of their complexity. Unlike chemical degradation rates in solution, physical degradation rates usually cannot be predicted on the basis of kinetic parameters estimated from data obtained under accelerated conditions. However, prediction of some physical degradation pathways such as polymorphic changes has been attempted. Several reports dealing with the prediction of polymorphic transitions...

Mechanism Of Cyclodisone Degradation

Wills, Oximes antagonistic to inhibitors of Cholinesterase, Part I, J. Pharm. Sci. 53, 995-1007 1964 . 2. T. D. Sokoloski, L. A. Mitscher, J. V. Juvarkar, and B. Hoener, Rate and proposed mechanism of anhydro-tetracycline epimerization in acid solution, J. Pharm. Sci. 66, 1159-1165 1977 . 3. B. A. Hoener, T. D. Sokoloski, L. A. Mitscher, and L. Malspeis, Kinetics of dehydration of epitetracycline in solution, J. Pharm. Sci. 63, 1901-1904 1974 . 4. G. L. Amidon,...

Isomerization and Racemization

Reported examples of isomerization of drug substances include trans-cis isomerization of amphotericin B Scheme 33 ,148 N,O-acyl rearrangement of cyclosporin A Scheme 34 ,149 and dienone-phenol rearrangement of steroids such as tirilazad Scheme 35 .150 Scheme 25. Hydrolysis of 5-azacytidine and cytarabine. Scheme 25. Hydrolysis of 5-azacytidine and cytarabine. Scheme 26. Other drug substances that are susceptible to hydrolysis, including alkyl halides, sulfides, and platinum compounds....