Acidic drugs solubility

An analysis of partition coefficient data and drug solubilities in PCL and silicone rubber has been used to show how the relative permeabilities in PCL vary with the lipophilicity of the drug (58,59). The permeabilities of copolymers of e-caprolactone and dl-lactic acid have also been measured and found to be relatively invariant for compositions up to 50% lactic acid (67). The permeability then decreases rapidly to that of the homopolymer of dl-lactic acid, which is 10 times smaller than the value of PCL. These results have been discussed in terms of the polymer morphologies. 

Generally it is only the non-dissociated or unionised drug that is lipid-soluble and a drug s degree of ionisation depends on its dissociation constant (pA) and the pH of the environment in which it finds itself. For an acidic drug this is represented by the Henderson Hasselbalch equation as... 

The derivation and experimental verification of the MMHS model represented a significant accomplishment and a natural plateau for film models. To be sure, there are general criticisms of film models and more specific criticisms of the MMHS model [6], However, overall the MMHS model should be recognized as a robust but simply applicable model which serves to demonstrate how factors such as intrinsic solubility of the acid drug, ionization and pA of the drug, and concentration of the reactive base all contribute to increasing the dissolution rate and mass transfer. 

An interesting paper that attempted to relate dissolution of a poorly soluble acidic drug (naproxen) to simulated gastrointestinal flow in the presence of buffers was published by Chakrabarti and Southard [17]. In addition to showing that buffer type (citrate, phosphate, or acetate) had a significant impact on naproxen dissolution, these authors unexpectedly found that elevating a solid tablet into the flow channel of the flow-between-two-plates apparatus resulted in a substantial... 

Other potential adverse effects include impaired absorption of fat-soluble vitamins A, D, E, and K hypernatremia and hyperchloremia GI obstruction and reduced bioavailability of acidic drugs such as warfarin, nicotinic acid, thyroxine, acetaminophen, hydrocortisone, hydrochlorothiazide, loperamide, and possibly iron. Drug interactions may be avoided by alternating administration times with an interval of 6 hours or greater between the BAR and other drugs. 

For even less soluble, weak acid drugs, the situation is not so simple, because the solubility even in biorelevant media is very low. A typical example is troglitazone, an antidiabetic... 

Figure 7 Behavior of two formulations of a poorly soluble, weakly basic drug (solubility characteristics shown in Figure 6) in media composed at two pHs—one to represent acidic conditions in the stomach, the other to represent the hypochlorhydric stomach. (A) Formulation with non-robust dissolution characteristics and (B) Formulation with robust dissolution characteristics.

Yazdanian, M., Briggs, K., Jankovsky, C., and Hawi, A., The "high solubility" definition of the current FDA guidance on biopharmaceutics classification system may be too strict for acidic drugs, Pharm. Res., 21, 293, 2004. 

It is common practice in pharmaceutical industry to generate salt forms of a drug substance to improve solid-state properties and solubility. CE has proven its ability to analyze reliably organic acids (direct, indirect detection) and alkaline/earth alkaline metals and basic amino acids. For basic drugs, a non-toxic organic acid or inorganic acid is chosen as counterion. Acidic drug substances will usually be deprotonated by alkaline and earth alkaline... 

Sulfonic Acids. Drugs that contain sulfonic acids are quite acidic. They have high water solubility and are rapidly excreted, leading to a rather short half-life. They can also be irritating to the gastrointestinal tract during the pharmaceutical phase. 

This strategy has limitations when the solubility (S) of the neutral drug molecule is very low. For an acidic drug molecule, an increase of one pH unit above the... 

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