How to Perform Solubility Studies for BCS Classification of Drugs?

The Biopharmaceutics Classification System (BCS) has shown to be extremely useful in the fields of drug discovery, product development, and regulatory sciences for pharmaceuticals. Solubility and intestinal permeability, the two main characteristics affecting oral medication absorption, are captured by the categorization scheme, which has shown to be a highly helpful and widely recognized starting point for drug product development and drug product regulation. The simplicity of BCS conceals several intricate nuances that must be assessed and looked into for each individual medication and drug product, both in vitro and in vivo.

The Biopharmaceutics Classification System (BCS) uses a number of factors to categorize drug substances (APIs), including dosage, human fraction absorbed, intestinal membrane permeability, and minimum water solubility in the pH range of 1-7.5.

Why BCS classification is important?
The goal of the BCS is to forecast how medicinal products will behave in humans based on in vitro assessments of their permeability and solubility.

In 2005, Wu and Benet observed that whereas medications with low intestinal permeability rates were mainly removed in humans as unmodified pharmaceuticals in the urine and bile, drugs with high intestinal permeability rates were predominantly eliminated in people through metabolism. They suggested that a biopharmaceutics drug disposition categorization system (BDDCS) may be used as a foundation for forecasting the significance of transporters in determining drug disposition and in forecasting drug-drug interactions.

The goal of BCS is to identify medications whose products could be qualified for a biowaiver of in vivo bioequivalence tests. The goal of BDDCS is to forecast how drugs will be disposed of and whether there will be any drug-drug interactions in the liver, gut, and maybe the kidney and brain. Solubility is one of the two categorization criteria used by BCS and BDDCS.

The solubility parameter utilized may be called the FDA solubility, that is, an estimate of the ability of the drug at its highest dose strength to completely dissolve in 250 ml of water over a pH range between 1 and 7.5 at 37°C. For a drug to be considered highly soluble in the two classification systems, the drug from its highest strength regulatory approved dosage form must go completely into the solution at its lowest solubility over this pH range in 250 ml of water. 

According to the FDA, solubility is a characteristic of the drug as a whole, not of the active pharmacological component in and of itself. Intestinal permeability is the second categorization parameter where the two systems diverge. Predictions in the BDDCS are based on intestinal permeability rate, which has been linked to the degree of drug metabolism. Biowaivers in BCS is determined by the degree of intestinal absorption, which frequently does not correspond to the intestinal permeability rate.

How to Perform Solubility Studies for BCS Classification of Drugs?
  • Accurately weigh and dissolve the API in aqueous buffer pH 1.2, Buffer pH 4.5, and Buffer pH 6.8 heated to 37 ± 1°C in a flask to obtain a saturated solution (Perform in triplicate, at each pH).
  • Measure and record the pH of the solutions
  • Secure the flask to the orbital shaker maintained at 37 ± 1°C employing an appropriate shaker speed.
  • Withdraw sample aliquots at different time points until equilibrium has been reached.
  • Samples should be filtered or centrifuged during or immediately after withdrawal to remove undissolved API.
  • Dilute the sample to avoid precipitation before quantifying.
  • Record pH and determine the concentration of the API in the solution at each time point.
  • Report solubility in mg/mL; Calculate dose: solubility volume (DSV) by dividing the highest therapeutic dose (in mg) by the solubility (in mg/mL) obtained in the study.
  • An API is considered highly soluble when the DSV is ≤ 250 mL over the entire pH range 1.2–6.8

Selection of Buffers
  • If there are any known solubility minima for the API in aqueous media within that pH range (for example the pKa of the API is within the tested pH range of 1.2–6.8), data should also be collected at that pH.
  • Aqueous pharmacopoeial buffer solutions are recommended for use in solubility experiments
  • Surfactants should be avoided in equilibrium solubility studies because they would produce biased results.

Shake Flask Method
  • The agitation speed of the shaker must be optimized based on the shape of the flask or tube and the volume of the liquid to prevent particle agglomeration and ensure particle contact with the diluent. Vortex formation should be avoided
  • Poor wettability of the API: It may be necessary to include tools such as glass microspheres to aid the de-aggregation of the particles with agitation or sonication.

Time to Equilibrium
  • Measure the concentration of the solution at different time points until it does not deviate significantly (e.g., 10%) between sequential measurement
  • Samples should be collected and analyzed at several time points (e.g., 2 hours, 4 hours, 8 hours, 24 hours, 48 hours, and 72 hours), until equilibrium has been reached
  • With an optimized agitation rate, it is expected that samples will generally reach equilibrium within 24 hours.

pH Adjustments
  • The pH of the buffers should be adjusted at the same temperature as that at which the equilibrium solubility experiments are performed, that is, at 37 ± 1°C.
  • Change in buffer pH on dissolving the API can be addressed by adjusting the pH with an appropriate acid or base solution or employing a buffer with a strong buffering capacity
  • After adjustment of the pH, the solution should be allowed to re-equilibrate for at least one hour before a sample is taken.

Analytical Method and Drug Stability
  • Validated, stability-indicating analytical method to be used to assay sample concentration; HPLC is generally used as it can detect impurities and instability. 
  • The relative standard deviation of the obtained solubility results should not be more than 10% between the replicates of each test condition
  • Degradation of the drug substance as a function of buffer composition and/or pH should be reported.

The study report template for equilibrium solubility is available at the link below.

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