formulation

An important rule for Drug selection for M.pharm Project- Lipinski’s Rule of five

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How do you select a Drug for your M.pharm / Ph.D project based on Lipinski’s rule?

Selection of drug for M.Pharm / Ph.D projects is a very tough task. Getting a New drug itself is a challenging task. Then again there is another problem if the drug you selected is not available in the market. We get a doubt whether the drug is suitable to be made into a tablet or an emulsion. Of course we can know this by bioavailability studies in mice or another animals (maybe humans if the drug is safe) but again how would you feel if at the end of the day you dont get the results you expected?

So before we select a drug for oral use , (this includes not only tablets, capsules, emulsions and suspensions but also novel systems including Liposomes, nanoparticles, Gastro retentive drug delivery systems (GRDDs) and so on,) we need to ensure that our drug satisfies the Lipinski’s rule of Five.

What is Lipinski’s rule of Five

Lipinski’s rule states that, in general, an orally active drug has no more than one violation of the following criteria:

  • Not more than 5 hydrogen bond donors (nitrogen or oxygen atoms with one or more hydrogen atoms)
  • Not more than 10 hydrogen bond acceptors (nitrogen or oxygen atoms)
  • A molecular mass less than 500 daltons
  • An octanol-water partition coefficient log P not greater than 5

How this rule benefits your project?

The rule describes molecular properties important for a drug’s pharmacokinetics in the human body, including their absorption, distribution, metabolism, and excretion (“ADME”). However, the rule does not predict if a compound is pharmacologically active.
  1. This rule helps Pharmaceutics/Industrial Pharmacy students in proper selection of the drug and knowing whether the drug is suitable for oral formulations.
  2. For Medicinal chemistry students involved in drug designing, CADD, understanding this rule will help you a lot in designing suitable homologues of rugs and fine tuning your drug with suitable modifications

An Example from Lipinski’s original paper

Quoting from Christopher A. Lipinski … “Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings”:

“In the USAN set we found that the sum of Ns and Os in the molecular formula was greater than 10 in 12% of the compounds. Eleven percent of compounds had a MWT of over 500. Ten percent of compounds had a CLogP larger than 5 (or an MLogP larger than 4.15) and in 8% of compounds the sum of OHs and NHs in the chemical structure was larger than 5.

The Lipinski “Rule of Five” states that compounds are likely to have good absorption and permeation in biological systems and are more likely to be successful drug candidates if they meet the following criteria:

  1. five or fewer hydrogen-bond donors
  2. ten or fewer hydrogen-bond acceptors
  3. molecular weight less than or equal to 500
  4. calculated logP less than or equal to 5

*Compound classes that are substrates for biological transporters are exceptions to the rule.

If two parameters are out of range, a “poor absorption or permeability is possible” alert is a very visible educational tool for the chemist and serves as a tracking tool for the research organization.

More Resources

For more information and understanding follow these related resources:

  1. A powerpoint illustrating the basics is here:  Lipinski
  2. Wikipedia’s page on Lipinski’s rule of five http://en.wikipedia.org/wiki/Lipinski’s_Rule_of_Five
  3. The original paper of Lipinski is titled “Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings” and is avaialable on Science direct here or here Direct download
  4. There is a page on Facebook (YES!!!) which can be found here

  5. Lipinski Rule-of-5 calculator in ChemDraw/Excel . Get it here or here