Drug stability optimum

Another important consideration when selecting the optimum formulation pH is the drug stability for pH sensitive drugs, such as peptides and proteins. Also, pH might affect the... 

Modification of Chemical Structure of Drug The use of a Hammett linear free-energy relationship to investigate the effects of substituents on the rates of aromatic side-chain reactions such as hydrolysis of esters has been alluded to earlier vis-a-vis attainment of optimum stability [9,10]. Degradation of erythromycin under acidic pH conditions is inhibited by substituting a methoxy group for the C-6 hydroxyl as found for the acid stability of clathromycin, which is 340 times greater than that of erythromycin [70]. 

Tetracycline antibiotics are generally considered relatively unstable compounds. Oxytetracycline posseses limited stability in aqueous solutions and shows specific and base catalysis, with overall hydrolysis observed to follow pseudo-first-order kinetics. The maximum stability of this drug is exhibited at pH 2, whereas the optimum stability ranges from pH 1 to 3, which accounts for the recent finding (70) that oxytetracycline has greater heat stability at pH 3 than at pH 6.9. 

In spite of the many studies on isolation, activity, and synthesis of natural antifeedants, the number of compounds commercially available remains low, often due to their cost of isolation, availability of the plant source, or low persistence in field conditions. To overcome these drawbacks, much research is conducted on structure—activity relationships (SAR). The rationale behind these studies is to discover the correlation between biological activity and chemical structure and to draw from that optimum structures having both the activity, stability, and selectivity for maximum feeding deterrence.4 5 SAR are much used in drug design6 and have been applied to insecticides.7... 

The techniques for predicting the chemical stability of homogeneous drug systems are well defined. " The formulation chemist should consider both the pH-solubility profile and the pH-stability profile when selecting the optimum pH for formulation of the liquid oral dosage form. For example. Figs. 3 and 4 show the... 

The optimum time of trituration must be determined individually for each active substance. Factors that must be taken into consideration include the dissolution rate, bioavailability, chemical and physical stability of the drug, and the costs. Usually one hour is adequate. 

As the data from Fig. 10.5 suggests, the PHis-PEG micelles are unstable and can release their contents at neutral pH. In order to deal with this problem, an amphiphilic block copolymer, PLLA-PEG, was added to make mixed micelles, in which the core was expected to contain poly(L-lactic acid) (PLLA) and PHis chains. The PLLA block in the core stabilized the micelles and hence suppressed the drug release at the near neutral pH. The optimum content of PLLA-PEG was found to be about 25 0% (Fig. 10.7). The DOX delivered from such mixed micelles showed low cytotoxicity at pH above 7.0 but high cytotoxicity at pH 6.8 [143]. 

A variety of factors need to be considered when selecting the optimum chemical form of a new drug candidate. These include all physicochemical properties which would influence physical and chemical stability, processability under manufacturing conditions, dissolution rate, and bioavailability. Such selection of chemical form must be done at the initial stages of development, when material and time are limited. Often the medicinal and process chemists select salt forms based on a practical basis, such as previous experience with the salt type, ease of synthesis, reaction yield, etc. Pharmaceutical considerations such as stability, handleability, hygroscopicity, and suitability for a specific dosage form may be secondary considerations. 

A preformulation package provides essential information on the physicochemical properties of the drug, such as pKa, aqueous solubility, aqueous stability, light stability, and lipophilicity (this may predict potential for binding to plastic/rubber pump components). The pK s of any ionisable groups are particularly important as they affect stability, solubility and lipophilicity and should indicate the optimum pH for the nasal solution. For physiological reasons, formulated products are usually in the range of pH 4.0-7.4. 

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