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State of matter and properties of matter (Part-10) (Physicochemical properties of drug molecule: Determination and Application 5. Dissociation constant)

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State of matter and properties of matter (Part-10) (Physicochemical properties of drug molecule: Determination and Application 5. Dissociation constant)

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DISSOCIATION CONSTANT: Definition, Henderson-Hasselbalch equation, Determination: 1.Conductivity method.
2.Solubility method. 3.Potentiometric method.
4.Spectrophotometric method, Application

DISSOCIATION CONSTANT: Definition, Henderson-Hasselbalch equation, Determination: 1.Conductivity method.
2.Solubility method. 3.Potentiometric method.
4.Spectrophotometric method, Application

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State of matter and properties of matter (Part-10) (Physicochemical properties of drug molecule: Determination and Application 5. Dissociation constant)

  1. 1. IIIrd Semesester B. pharmacy Physical Pharmaceutics-I Unit-II State of matter and properties of matter (Part-10) (Physicochemical properties of drug molecule: Determination and Application 5. Dissociation constant) Miss. Pooja D. Bhandare (Assistant professor) Kandhar college of pharmacy
  2. 2. DISSOCIATION CONSTANT • Definition: tendency of a particular substance in solution is to reversibly dissociate into ions. • Also know as ionization constant. • It is equal to the product of respective ion concentration non ionic molecule. • The greater the dissociation constant of the acid, the stronger is the is the acid • Ka or acid dissociation constant is a quantitative measurement
  3. 3. • Let us consider the dissociation of the compound ‘HA’ • The Ka for this reaction will be given by: • Expressing acidity in terms of Ka can be inconvenient for practical purposes, therefore pKa is used
  4. 4. • pKa can be defined as ‘the negative base -10 logarithm of acid dissociation constant (Ka) of a solution. • pKa = -log10Ka • Example: The Ka constant for acetic acid is 0.0000158, but the pKa constant is 4.8, which is a simpler expression. • The smaller the pKa value, the stronger the acid. • The pKa value of lactic acid is about 3.8, so that means lactic acid is stronger than acetic acid. • A weak acid has a pKa value the approximate range of -2 to 12 in water • Acids with a pKa value of less than about -2 are said to be strong acid. • The unionized drug is lipid soluble thus permeates through lipid membrane. • The ionized substance is lipid insoluble therefore permeation is slow.
  5. 5. • Degree of ionization depends on pH • Henderson-Hasselbalch equation: • For basic compounds: pH = pKa + [𝒊𝒐𝒏𝒊𝒛𝒆𝒅} [𝒖𝒏−𝒊𝒐𝒏𝒊𝒛𝒆𝒅] • For acidic compounds: pH = pKa + [𝒖𝒏−𝒊𝒐𝒏𝒊𝒛𝒆𝒅] [𝒊𝒐𝒏𝒊𝒛𝒆𝒅𝒔]
  6. 6. Determination 1. Conductivity method. 2. Solubility method. 3. Potentiometric method. 4. Spectrophotometric method
  7. 7. 1. Conductivity method • The law is based on the fact that only a portion of electrolyte is dissociated into ions at ordinary dilution and completely at infinite dilution. • Weak electrolytes are partially dissociate in solution. Hence for such electrolytes the dissociation constant (Ka) is given by Ostwald’s dilution law as follows: • • Where C= the molar concentration, α = degree of dissociation. • The value of α is given as the ratio of the equivalent conductivity of the electrolyte at a particular concentration to that at infinite dilution. i.e. α = γv
  8. 8. 2. Solubility method • A derivation of the Henderson- Hasselbalch equation allows us to determine the pKa from solubility data. • log S = logSo + log(10−𝑝𝐾𝑎−𝑝𝐻 + 1) • Here S0 is equal to the intrinsic solubility. • When pH>> pKa or pH<< pKa assumptions can be made and linear logS/pH function are obtained. • By extrapolating these two function and calculating the intercept, the pKa can be calculated: • log S = (logS0- pKa) + pH
  9. 9. 3. Potentiometric method • In potentiometric titration, a sample is titrated with acid or base using pH electrode to monitor the course of titration. • The pKa value is calculated from the change in shape of the titration curve compared with that of blank titration without sample is present. • Relationship between pH and pKa: pH = pKa + log10 [𝐴‫־‬] [𝐻
  10. 10. 4. Spectrophotometric method • Main advantages is higher sensitivity. • The compound must contain a UV- active chromophore close enough to the site of the acid-base function in the molecule. • Spectral data are recorded continuously during the course of titration by a diode-array spectrometer. • The absorption spectra of the sample changes during the course of the titration to reflect the concentration of neutral and ionized species present.
  11. 11. • The largest changes in absorbance occurs at the pH corresponding to a pKa value. • The determine of pKa values by UV-VIS assumes that the solute of interest is pure or that its impurities do not absorb in the UV-VIS range, since the spectra of impurities can overlap with those corresponding to the solute of interest.
  12. 12. Application 1. Dissociation constant is incorporated in Henderson-Hasselbalch equation to calculate the extent of ionization (or dissociation), i.e per cent unionized and ionized forms of drug. 2. The absorption of drugs in gastrointestinal tract can be predicted using dissociation constant of the drug and pH at different sites of GIT. 3. The concentration of preservatives such as benzoic acid required to preserve solution and emulsion can be predictes.
  13. 13. 4. The pH of the solution can be calculated. When the concentration of acid is equal to the concentration of salts, the pH of the solutions is same as the pKa of the drug. 5. Ionization constant values can be used to obtain maximal yields in the extraction of drugs. In most cases, the substance is in a dissolved state as a salt in the aqueous medium. The pH of the solution is adjusted to a value of 2 units on far sides of the pKa. In this process entire substance is insoluble in water. Thus maximal yield of substance can be obtained. For these reasons, pKa value of a new substance is determined in very early stages of the development work.
  14. 14. Thank you!

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