Drug solubility stomach

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.

No basal acid secretion in the stomach during fasted state, and thereby often close to neutral pH in contrast to the acidic human pH. However, an acidic pH may be induced in some individuals without intake of food. This has to be specially considered, for example, when drug solubility is pH dependent and for enteric-coated formulations, for which drug release is dependent on the pH in the GI tract. 

In the stomach and intestine, drug solubility can be enhanced by food and bile components such as bile salts, lecithin, and fatty acids. Supersaturation in the intestinal fluid is an important property that can play a significant role in drug absorption. For compounds with poor intrinsic solubility in the intestinal fluid, solubility is often a limiting factor for absorption. For many of these compounds, it may not be possible to enhance the saturation solubility to the extent required such that the whole dose is dissolved in the GI fluid. In this case, creating or maintaining supersaturation in the intestinal fluid can be an effective way to enhance absorption of these compounds (Wei-Qin 2009). 

Figure 5,4 Pharmacokinetics. The absorption distribution and fate of drugs in the body. Routes of administration are shown on the left, excretion in the urine and faeces on the right. Drugs taken orally are absorbed from the stomach and intestine and must first pass through the portal circulation and liver where they may be metabolised. In the plasma much drug is bound to protein and only that which is free can pass through the capillaries and into tissue and organs. To cross the blood brain barrier, however, drugs have to be in an unionised lipid-soluble (lipophilic) form. This is also essential for the absorption of drugs from the intestine and their reabsorption in the kidney tubule. See text for further details...

The solubility should be measured at all of these pH values with a suitable, validated method such as shake-flask or pSol (2) at 37°C to determine whether the (envisaged) dose of the drug can be completely dissolved at all points of interest in the GI tract (see Chapter 11 for more discussion of solubility determination). Typically, this would be the upper GI pH (stomach and proximal small intestine) for immediate release (IR) products, the pH in the small intestine for enteric-coated products and, additionally for MR dosage forms intended to release over a period of six hours or more, the pH in the proximal colon. 

As a result, if dissolution from formulations is studied exclusively under low pH conditions, the formulators are likely to be in for a rude shock when the results come back from the pharmacokinetic studies—poor and highly variable absorption is the order of the day for drugs that have been formulated without an eye to robustness of the release from the dosage form as a function of pH. Instead, it is recommended that a formulation be sought that can release the drug even when there is not enough acid in the stomach to provide a sufficient boost to the solubility or when the gastric residence time is short. 

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