Free base, drug formulation

The addictiveness of a given substance goes beyond the chemical structure of the addictive drug itself (i.e., morphine, cocaine, or nicotine). The effects are also related to the dose and speed of delivery, as well as to other substances that might be part of the formulation. For example, just as the oral consumption of opioids and cocaine produce substantially less pronounced behavioral and physiological effects than intravenous or smoked consumption, slow release forms of nicotine produce generally less pronounced effects than smoked forms (Henningfield and Keenan 1993). Similarly, the free base or unprotonated forms of cocaine and... 

A different mechanism for dissolution slowing was reported for delavirdine mesylate tablets (81). In this direct compression formulation, the methane sulfonic acid from the drug was shown to react with the disintegrant croscarmellose sodium to form the free acid of croscarmellose and the poorly soluble delavirdine free base. The authors conclude that similar reactions could occur for any acid salt of a basic drug. 

Insoluble salts may be prepared using high molecular weight counterions to reduce the solubility of the drug for formulation of a suspension, to improve chemical stability, provide improvements in solid-state stability, reduce acid lability and permit formulation of tasteless or controlled release products. Erythromycin stearate, which is poorly soluble in acidic media (an enteric salt), is less prone to decomposition in gastric fluids than the more acid-soluble free base. 

The depot FGAs fluphenazine decanoate (also available in an enanthate salt) and haloperidol decanoate are esterified drugs formulated in sesame seed oil for deep intramuscular injection. Their absorption from the muscle and metabolism to the free base is sufficiently slow to cause absorption to be the rate-limiting step in determining their respective apparent half-lives. ... 

The aqueous solubility of indinavir is pH dependent, with increased solubility at acidic pH. During development, the compound was initially used in the free base monohydrate form and its absorption kinetics was tested in rats and dogs in two separate formulations of (i) 0.5% methocel suspension and (ii) 0.05 M citric acid solution, for an oral dose of 10 mg kg In rats, indinavir attained a C ax value of 0.56 pM in 15 min in the methocel formulation, almost similar to that in citric acid (C ax 0-44 pM in 35 min). In dogs, there were more prominent differences in the two formulations. The C ax value in methocel suspension was 3.72 pM in 25 min as opposed to 11.4 pM in 30 min in the citric acid solution. It was also observed that the bioavailability of indinavir in both rats and dogs was quite similar ( 16%) when administered as a 10 mg kg dose in methocel suspension. However, in 0.05 M citric acid solution, the bioavailability of the drug in dogs was approximately 33% higher than that in rats. 

Liposomal encapsulation or incorporation in a lipid complex can substantially affect a drug s functional properties relative to those of the unencapsulated or nonlipid-associated drug. Lipid-based formulations increase the circulation time and alter the biodistribution of associated amphotericin. Increasing drug levels at site of action and reducing levels in normal tissues offers 2 distinct clinical advantages An increased therapeutic index and altered toxicity profile relative to free drug. 

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