Solutions drug stability

Fig. 6 Solubility effects on drug stability curve A, drug formulated as lOmg/mL solution (q/2 = 1 year) curve B, drug formulated as a suspension with a saturated solubility of 1 mg/mL (ti/2 = 7.3 years). 

Higuchi and Lachman [122] pioneered the approach of improving drug stability by complexation. They showed that aromatic esters can be stabilized in aqueous solutions in the presence of xanthines such as caffeine. Thus, the half-lives of benzocaine, procaine hydrochloride, and tetracaine are increased by approximately two- to fivefold in the presence of 2.5% caffeine. This increase in stability is attributed to the formation of a less reactive complex between caffeine and the aromatic ester. Professor K. A. Connors has written a comprehensive textbook that describes methods for the measurement of binding constants for complex formation in solution—along with discussions of pertinent thermodynamics, modeling statistics,... 

Behind the relatively straightforward compositional nature of ophthalmic solutions, suspensions, and ointments, however, lie many of the same physicochemical parameters that affect drug stability, safety, and efficacy, as they do for most other drug products. But additionally, specialized dosage forms present the ophthalmic product designer with some extraordinary compositional and manufacturing challenges. These... 

Nebulizer formulation conforms to sterile product preparation, which means that drug stability in solution in the presence of additives must be evaluated. Historically, it was sufficient to use antimicrobial agents in the formulation, notably benzalkonium chloride. Adding antimicrobials is not now considered an acceptable approach to the formulation of nebulizer solutions. The solubility of the drug is important since it may impact upon the performance of the solution in a selected nebulizer. Additives may form complexes with the drug. 

Oral Easy Convenient Acceptable Painless Self-administration possible Inappropriate during vomiting Potential drug-stability problems Interactions with food Possible low availability Patient must be conscious Solutions, syrups, suspensions, emulsions, powders, granules, capsules, tablets... 

Eormulation is an experimental stage in development to set specifications for the final product that will be sold and administered to patients. Studies must, therefore, be conducted to provide production limits for the product. A solution may require a specific pH for drug stability, for example, pH 7.0, so experiments will also be conducted at pH 6.5 and pH 7.5. If the drug is also stable at these two pH values, then the pH limits for the drug product can be set around the desired value of pH 7.0. Similar experiments... 

Carstensen, J. T. (2000), Solution Kinetics Kinetic pH profiles Oxidation in solution Catalysis, Complexation, and Photolysis, in Carstensen, J.T. and Rhodes, C.T., Eds., Drug Stability, Principle and Practice, 3rd ed., Marcel Dekker, New York, Chapters 2-5, pp. 19-143. 

Solution-based systems are common to both nebulizers and nasal formulations. In general, water will form the greatest fraction of the formulation, but, in some cases, cosolvents such as ethanol and propylene glycol may be added for increased stability. Acidifying and alkalizing excipients may also be added to optimize pH from the perspective of the drug stability as well as the physiological effect on the airways. Similarly, iso-osmotic and iso-tonic solutions are preferred. 

Jn drug stability studies, the rates of hydrolysis of indomethacin (Sigma-Chem.) were considerably slower in Pluronic F 127 (BASF) gels than in buffer alone. The degradation of indomethacin followed 1st order kinetics, with linear plots of the 1st order rate constant vs. pH in both Pluronic and aqueous solutions, allowing prediction of the time required for degradation of indomethacin."... 

Asker AF, Habib MJ. Effect of certain stabilizers on the photobleaching of riboflavin solutions. Drug Dev Ind Pharm 1990 16(1) 149-156. 

Habib MJ, Asker AF. Influence of certain additives on the photo-stability of colchicine solutions. Drug Dev Ind Pharm 1989 15(5) 845-849. 

Gallelli JF. Assay and stability of amphotericin B in aqueous solutions. Drug Intell 1967 1 103-105. 

Type of drug product (capsule, tablet, solution, etc.) Stability... 

Loftsson, T. Effects of cyclodextrins on the chemical stability of drugs in aqueous solutions. Drug Stab. 1995,1 (1), 22-33. 

Cartensen, J.T. Solution kinetics. In Drug Stability Principles and Practices Marcel Dekker, Inc. New York, 2000 19-56. 

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