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How It All Gets Absorbed
David W. Newton, BS Pharm, PhD, FAPhA, Professor
Department of Biopharmaceutical Sciences
Bernard J. Dunn School of Pharmacy
Shenandoah University
Winchester, Virginia
Introduction
In the spring of 2007, a first-year PharmD student asked the following terrific question:
If a drug diffuses most readily through cell membranes in its non-ionized form, but it must be ionized for its best solubility in small intestinal contents, then what exactly takes place so that the drug gets absorbed?
Her question was from the case I assigned to her group of six students to explain how an 800-mg oral dose of ibuprofen can be completely absorbed when only 25 mg is dissolved in gastric contents at any one moment and more than 95% is ionized at pH 6 in the small intestine lumen. The short answer was published in a journal letter1 but is detailed hereafter for 800 mg of ibuprofen and 20 mg of diazepam orally.
Dissolution, Diffusion, and Solubility of Weak Electrolyte Drugs
Weak electrolytes are organic compounds that exist concurrently in both an acid and base form, and an ionized and non-ionized form. The extents of those conjugate pairs depend on solution pH and the pKa of the acid form as expressed in the Henderson-Hasselbalch equation. At the pH equal to the pKa, a weak electrolyte exists 50% each in its acid and base forms, one of which is ionized and the other which is non-ionized.
Table 1 presents the symbols, Henderson-Hasselbalch formulas, and solubility equations for ibuprofen and diazepam, which typify drugs that contain aromatic rings (i.e., most drugs).2 The non-ionized form, whether it be an acid or a base, diffuses passively through biological or plasma membranes because of the predominant lipophilicity of non-ionized molecules and membrane lipids.3-5 Conversely, the ionized form exhibits the fastest dissolution rate and greatest solubility extent in water and aqueous fluids.4-6
The solubility of non-ionized acids, HA, increases exponentially as pH values above their pKa increase their ionization until reaching the total or saturated solubility of the ionized or salt form, and the solubility of non-ionized or free bases, B, increases exponentially as pH values below the pKa of their acid form increase their ionization until reaching the total or saturated solubility of the ionized or salt form.4,7 The total solubility, ST, of salts that consist of active drug ions containing aromatic rings and balancing inorganic or non-aromatic organic ions is usually achieved at greater than 90% and less than 99.9% of the ionized form. Thus, the ST equations in Table 2 fail for HA ↔ A- conjugate acid ↔ base pairs when (Ka/[H3O+])>1000 or pH >(pKa + 3), and for BH+ ↔ B conjugate acid ↔ base pairs when ([H3O+])/Ka)>1000 or pH<(pKa - 3). Drug salts in which both ions contain aromatic rings do not obey the ST equations because of non-dissociable London dispersion or induced dipole-induced dipole intermolecular forces between the carbon atoms in the aromatic rings.2
How It All Gets Absorbed
The chemical, physical, and biopharmaceutical values for ibuprofen and diazepam that are relevant to this article are summarized in Table 2. The data in Table 3 represent immediate release oral dosage forms of ibuprofen and diazepam in the stomach and jejunum with an assumed 150 mL of fluid available are free to dissolve the drugs (i.e., water not bound chemically or physically with food residues). Most orally ingested drugs, nutrients, and other chemicals initially enter the bloodstream by molecular diffusion from small intestine contents into membrane capillaries.3 The concurrent phenomena depicted in the Scheme that accompanies this document are the following:
- Dissolved non-ionized acid HA ibuprofen and base B diazepam diffuse from small intestinal contents into membrane capillaries. This creates a "sink" or "open drain" condition in which drug accumulation in the systemic bloodstream is limited by continual removal of drug via metabolism and/or elimination.
- Dissolved anionic base form, A-, of ibuprofen and cationic acid form, BH+, of diazepam instantly convert to dissolved HA and B, respectively, to maintain their constant acid to base concentration ratios, A-/HA and B/BH+, at the local pH. At any pH for any weak electrolyte, the Henderson-Hasselbalch equation maintains a constant ratio of the base to acid forms:
pH = pKa + log ([base]/[acid])
thus
([base]/[acid]) = 10(pH-pKa)
As dissolved A- and BH+ replace dissolved HA and B that diffuses in step 1, the total dissolved concentrations of (HA+A-) and (BH+ + B) in intestinal contents decline.
- Undissolved HA and B dissolve to replace the dissolved drugs converted in step 2, which replaced the dissolved drug diffused or "lost" to blood in membrane capillaries in step 1.
Summary
These relatively fast diffusion-dissolution equilibria are applicable to all weak electrolyte drugs for which oral bioavailability is greater than 50% and solubility of the non-ionized form in intestinal contents is less than the ingested dose. A simplistic portrayal of these concurrent and thermodynamically interdependent equilibria is that the "sink" diffusion in step 1 ultimately "pulls" undissolved drug in intestinal contents in step 3 into solution in step 2.5
References
- Newton DW. Science-based pharmacy education. Am J Pharm Educ 2007; 71(2) Article 38. Available at: http://www.ajpe.org/view.asp?art=aj710238&pdf=yes.
- Newton DW. Drug incompatibility chemistry. Am J Health-Syst Pharm 2009; 66: 348-357, 1431.
- Bruton LL, ed.; Lazo JS, Parker KL, assoc. eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 11th ed. New York, NY; McGraw-Hill; 2006: 2-3, 5, 1816, 1834.
- Allen LV Jr, Popovich NG, Ansel HC. Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, 9th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2011: 100-108, 332-335.
- Cadwallader DE. Biopharmaceutics and Drug Interactions. 3rd ed. New York, NY: Raven Press; 1983: 49-58.
- Berge SM, Bighley LD, Monkhouse DL. Pharmaceutical salts. J Pharm Sci 1977; 66: 1-19.
- Troy DB, ed. Remington: The Science and Practice of Pharmacy. 21st ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005: 215.
- Dressman J. The BCS: Where do we go from here? Pharm Technol 2001; 45: 68, 70, 72, 74, 76.
- Newton DW, Driscoll DF, Goudreau JL et al. Solubility characteristics of diazepam in aqueous admixture solutions: Theory and practice. Am J Hosp Pharm 1981; 38: 179-182.
Table 1. Acid and Base Symbols and Henderson-Hasselbalch Equations for Ibuprofen and Diazepam.2
| Parameter | Symbol or Equation |
| Ibuprofen | Diazepam |
| Acid form | HA | BH+ |
| Base form | A- | B |
| Non-ionized form | HA | B |
| Ionized form | A- | BH+ |
| Fraction of acid forma | 1/(1+10[pH-pKa) | 1/(1+10[pH-pKa) |
| Fraction of base forma | 1-fraction of acid form | 1-fraction of acid form |
| aMultiply by 100 for percent. |
Table 2. Chemical and Physical Constants and Mean Oral Pharmacokinetic Values for Ibuprofen and Diazepam.
| Parameter | Value |
| Ibuprofen | Diazepam |
| Intrinsic solubility of non-ionized form, mg/mL | 0.0648a | 0.059b |
| pKa | 4.398c | 3.39d |
| Ka | 4.074×10-5e | 5.012×10-4f |
| Total solubility, ST, equation | ST = SHA{1+(Ka/[H3O+])}g | ST = SB{1+([H3O+])/Ka)}g |
| Oral bioavailability, % | >803 | 85 to 1003 |
| Time to maximum plasma concentration, hr | 1 to 23 | 1 to 1.53h |
aSaturated solubility, SHA, in water
bSaturated solubility, SB, in water
cHA ↔ H+ + A- equilibrium
d BH+ ↔ B + H+ equilibrium
eKa = 10-4.39
fKa = 10-3.3
g[H3O+] = 10-pH
hImmediate or non-controlled release oral dosage forms |
Table 3. Extents of Acid and Base Forms, and Solubilities of Ibuprofen and Diazepam at pH 2 and pH 6 Relative to 800-mg and 20-mg Doses, Respectively.
| Variable | pH 2a | pH 6b |
| Ibuprofen | Diazepam | Ibuprofen | Diazepam |
| Percent as non-ionized form | 99.6c | 4.8d | 2.4c | 99.8d |
| Percent as ionized form | 0.4c | 95.2d | 97.6c | 0.2d |
| Total solubility, ST, mg/mL | 0.064e | 1.05f | 2.7g | 0.05h |
| Dissolved amount of non-ionized form per 150 mL, mg | 9.6i | 7.6j | 0.2k | 7.5l |
| Dissolved amount of ionized form per 150 mL, mg | 0m,n | 12.4o | 404.8p | 0n,q |
| Undissolved amount of non-ionized form per 150 mL, mgr | 790.4 | 0 | 395 | 12.5 |
aSuch as in fasting stomach lumen
bSuch as in jejunum lumen
cPercent as HA = 100/(1+10[pH-pKa]); percent as A- = 100 - percent as HA
dPercent as B = 100/(1+10[pKa-pH]); percent as BH+ = 100 - percent as B
eST = SHA{1+(Ka/[H3O+])} = 0.064 mg/mL{1+(4.074×10-5/[1×10-2])} = 0.064 mg/mL
fST = SB{1+([H3O+])/Ka)} = 0.05 mg/mL{1+([1×10-2]/5.012×10-4)} = 1.05 mg/mL
gST = SHA{1+(Ka/[H3O+])} = 0.064 mg/mL{1+(4.074×10-5/[1×10-6])} = 2.7 mg/mL
hST = SB{1+([H3O+])/Ka)} = 0.05 mg/mL{1+([1×10-6]/5.012×10-4)} = 0.05 mg/mL
iST(150 mL)(percent HA/100) = 0.064 mg/mL(150 mL)(0.996) = 9.6
jST(150 mL)(percent B/100) = 1.05 mg/mL(150 mL)(0.048) = 7.6
kST(150 mL)(percent HA/100) = 2.7 mg/mL(150 mL)(0.024) = 0.23
lST(150 mL)(percent B/100) = 0.05 mg/mL(150 mL)(0.998) = 7.6
m(ST[150 mL]-dissolved amount of non-ionized form per 150 mL)
nThere is a miniscule fraction of ionized form present, but it was rounded to 0 for this table
o(20 mg dose-7.6 mg dissolved B form) = 12.4 mg
p(ST[150 mL]-dissolved amount of non-ionized form per 150 mL)
q(ST[150 mL]-dissolved amount of non-ionized form per 150 mL)
r(Dose ingested-total dissolved in 150 mL) |
Scheme. Concurrent Three-step Diffusion and Dissolution Equilibrium of Ibuprofen 800 mg and Diazepam 20 mg Orally.
| Jejunum Contents (e.g., 150 mL fluid at pH 6) | Blood in Capillaries, pH 7.4 |
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0.01 %BH+ ↔ 99.99% Bc
0.1% HA ↔ 99.9% A-c |
aSee footnote n to Table 3.
bpH = pKa + log ([base]/[acid]); thus, ([base]/[acid]) = 10(pH-pKa)
cPercent as BH+ and HA = 100/(1+10[pH-pKa]); % as B or A- = 100-% BH+ or HA. |
Key to symbols: B, diazepam non-ionized or free base; BH+, diazepam ionized (cationic, protonated) acid; HA, ibuprofen non-ionized acid; and A-, ibuprofen ionized (anionic) base.
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