Physical & Chemical Factors for Drugs to be Noted When Designing OCR

An oral controlled-release(OCR) drug refers to an oral formulation which can continuously release a drug for a long period of time after taking, wherein the main drug is slowly released and absorbed at an appropriate rate. The OCR drug needs to be taken less frequently, which is beneficial for reducing the side effects caused by exceeding the therapeutic blood concentration range, and it can be preserved in an effective concentration range for a long time to maintain the therapeutic effect.

Not all drugs are suitable for controlled-release dosage form. In the development of this form, the clinical needs, the physical and chemical properties of the drug, the influence of the physiological state of the gastrointestinal tract on the absorption of the drug, and the pharmacodynamics of the drug should be systematically considered. Regarding the physical and chemical factors of drugs, the following four points need to be noticed by developers.


  • Dosage size. A single dose of 0.5 to 1.0 g is generally the maximum dose of a conventional oral dosage form, which is also applicable to OCR drugs. With the development of formulation technology, many of the currently marketed tablets have exceeded this limit. However, as an oral dosage form, the dose size cannot be increased indefinitely. For large doses of the drug, multiple tablets can be taken at a time to achieve an effective dose. In addition, for drugs with a low therapeutic index, it must be considered that taking too much dose may cause safety problems.
  • PKa, degree of dissociation and water solubility. Most drugs that are absorbed by passive transport in the body are weak bases or weak acids. In general, non-dissociated, fat-soluble drugs readily pass through lipid biofilms. The pH of the gastrointestinal tract and the pKa of the drug directly affect the degree of dissociation of the drug in the gastrointestinal tract. Since OCR drugs generally require release of the drug in an environment where the pH of the gastrointestinal tract changes, it is important to understand the relationship between pK and the absorption environment, and the effect of pH on the drug release process must be studied.
    The rate of absorption of a drug with a low solubility (<0.01 mg/ml) in the gastrointestinal tract is limited by the rate of dissolution, and thus it has an intrinsic sustained release effect. The literature reports that the lower limit of the drug solubility requirement for the controlled-release form is 0.1 mg/ml.
  • Distribution coefficient. Drugs must be absorbed through various biofilms before they produce therapeutic effects in the body. The gastrointestinal epithelial cell membrane is a lipid membrane, and the partition coefficient of the drug determines whether it can effectively penetrate the biofilm. Drugs with a high partition coefficient are highly soluble in fat. These drugs can be concentrated in the lipid membrane of cells and usually stay in the body for a long time. It is difficult to pass a drug through a membrane with a small partition coefficient, and the bioavailability is generally poor. Maintaining an appropriate oil-water partition coefficient gives the desired amount of biofilm permeation.
  • Stability. Oral drugs are subjected to both acid-base hydrolysis and enzymatic degradation in the gastrointestinal tract. For solid drugs, the degradation rate is slowed down. Therefore, for a drug having a stability problem, the preparation may be in a solid state or other administration routes may be selected.