Weak bases, drugs

A phase solubility method was described by Dittert et al. (1964) to generate data that demonstrate the sensitivity of solubility to pH that is exhibited by weak acid and weak base drugs. Kramer and Flynn (1972) presented equations that deLne the aqueous solubilities of organic hydrochlorides. At low pH, the solubility, S, is the sum of the concentration of the organic base, [B], and the intrinsic solubility of its protonated form, [BH]0, as described in the following equation ... 

Most weak acid drugs as well as weak base drugs are absorbed primarily from the small intestine after oral administration because (A) Both types are more ionized in the small intestine Both types are less ionized in the small intestine... 

The proportion of ionized and unionized forms of a chemical compound can be readily calculated according to the above equation. It can be easily seen that pK is also a pH value at which 50% of the compound exists in ionized form. The ionization of weak acids increases as the pH increases, whereas the ionization of weak bases increases when the pH decreases. As the proportion of an ionized chemical increases, the diffusion of the chemical through the biological membranes is greatly impaired, and this attenuates toxicokinetic processes. For example, the common drug acetosalicylic acid (aspirin), a weak acid, is readily absorbed from the stomach because most of its dose is in an unionized form at the acidic pH of the stomach. 

VMATs are not inhibited by drugs such as cocaine, tricyclic antidqnessants and selective serotonin reuptake inhibitors that affect plasma membrane monoamine transport. Amphetamines have relatively selective effects on monoaminergic cells due to selective uptake by plasma membrane monoamine transporters, but their effect appears to be mediated by their ability as weak bases to reduce ApH, the driving force for vesicular monoamine transport that leads to efflux of the vesicular contents into the cytoplasm. 

A variety of drugs have been developed that act as sedatives, antidepressants, or stimulants some of these are effective in treating psychiatric disorders. Many of these drugs are weak bases. Examples are barbiturates such as phenobarbital, tranquilizers like diazepam (Valium), and amphetamines derived from phenylethylamine. 

Thus, as the pH increases, the dissolution rate of a weak base decreases. Referring to Table 2, we can see that, for the weak acid tolbutamide, the dissolution rate increases as pH is increased, as predicted by Eq. (3). Additionally, for the weak base tetracycline, as predicted by Eq. (4), the dissolution rate decreases as pH is increased. Thus far, the more rapid dissolution of the salt forms of these drugs and the direction of change of the dissolution rate with pH have been accounted for with Eqs. (1) to (4). However, there are six possible dissolution rate... 

The preparation of salts of organic compounds is one of the most important tools available to the for-mulator. Compounds for both IM and IV solutions may require high solubility in order for the drug to be incorporated into acceptable volumes for bolus administration (see Table 1). Sodium and potassium salts of weak acids and hydrochloride and sulfate salts of weak bases are widely used in parenterals requiring highly soluble compounds, based on their overall safety and history of clinical acceptance. 

Figure 5.1 shows a tetrad of equilibrium reactions related to the partitioning of a drug between an aqueous environment and that of the bilayer formed from phospholipids. (Only half of the bilayer is shown in Fig. 5.1.) By now, these reaction types might be quite familiar to the reader. The subscript mem designates the partitioning medium to be that of a vesicle formed from a phospholipid bilayer. Equations (4.1)-(4.4) apply. The pAi m in Fig. 5.1 refers to the membrane pKa. Its meaning is similar to that of pAi when the concentrations of the uncharged and the charged species in the membrane phase are equal, the aqueous pH at that point defines pAi em, which is described for a weak base as...

Figure 7.28b shows that membrane retention is very systematically increased for almost all of the weak bases. This is a general pattern for bases with any of the negatively charged membrane models, and is probably best explained by the increased electrostatic attractions between the drugs and the membranes. Still, all retentions are below 50%, due to the offsetting sink condition created in the acceptor wells. 

The convective diffusion approach for weak basic drugs dissolving in acidic media was previously derived by Litt and Serad [9] and, as shown by McNamara and Amidon, could be applied to dissolution of the free base of papaverine. 

---