Biorelevant Media l Hydrodynamics in the GIT l API/Formulation properties

                                     

Biorelevant Media l Hydrodynamics in the GIT   l  API/Formulation properties

How a medicine should be taken is usually explained in the patient information leaflet provided by the manufacturer. Whether a drug is taken before or after a meal can have a big impact on its absorption because food changes the properties of gastrointestinal fluids a lot. Gut fluids in both fasted and fed states are simulated by Biorelevant Media.

I have already shared the information regarding Fluid composition in the GIT. More details refer link

https://pharmatutor21.blogspot.com/2021/01/biorelevant-dissolution-media.html

 

This blog will help you to understand other two steps i.e. Hydrodynamics in the GIT and API/formulation properties

Biorelevant dissolution medium

Before the development of biorelevant dissolution medium the following steps should be considered

1)         Fluid composition in the GIT

2)         Hydrodynamics in the GIT

3)         API/formulation properties

4)         Prediction of plasma profile

5)         Development of IVIVCs

 

2) Hydrodynamics:

The dissolution fluid flow characteristics should consist of a predictable pattern that is free of irregularities or variable turbulence. Hydrodynamics is predominant for the overall dissolution rate if the mass transfer process is mainly controlled by convection/diffusion as is usually the case for poorly soluble substances. A thorough knowledge of hydrodynamics is useful in the course of dissolution method development and formulation development for pharmaceutical industries quality needs. The dissolution apparatus used for different formulation are shown in Table 1.

Table 1: Apparatus used for different formulation

Types of dosage form	Release method
Solid oral dosage form	Basket, paddle, reciprocating cylinder
Implants	Modified flow through cell
Chewing gum	Special apparatus
Powders & granules	Flow through cell

 For more details about the dissolution apparatus used for different formulation refer the link

https://pharmatutor21.blogspot.com/2021/01/different-dissolution-testing-apparatus.html

Muscular contraction in the wall of the small intestine achieve two objectives one is stirring of the contents to increase exposure to enzymes and to bring the luminaly digested products close to the wall and second propulsion of indigestible material towards the distal gut.

3) API/Formulation characteristics

Knowledge of the physiochemical nature of a compound in biorelevant media is useful for formulation development, which follows API phase selection. Based on this information the pKa profile of compound could be improved by modifying the surfactants or excipients in the formulation. Many new chemical entities possess physiochemical characteristics unfavorable for oral absorption.

·       BCS:

A biopharmaceutical classification system is a scientific framework for classifying the drug substance based on their aqueous solubility and intestinal permeability. The BCS was first devised in 1995, by Amidon et al and since then it has become a benchmark in the regulation of bioequivalence of oral drug products. According to BCS classification drugs can be categorized as follows

Class 1: High solubility and high permeability

Class 2: Low solubility and high permeability

Class 3: High solubility and low permeability

Class 4: Low solubility and low permeability

For drugs belonging to class 1 and 3, simple aqueous media such as SGF and SIF (with or without enzymes) are suggested. In contrast for class 2 and 4 use of biorelevant media is recommended for dissolution testing. There are various methods of determination of solubility and permeability.

For more details of BCS classification, refer link

https://pharmatutor21.blogspot.com/2021/01/the-biopharmaceutics-classification.html

·       Solubility:

Solubility is a crucial parameter for successful drug development as poor solubility compromises the Pharmacokinetic and Pharmacodynamic properties of drug. Drug solubility testing in biorelevant media has become an indispensable tool in pharmaceutical development.

Solubility can be measured either thermodynamically or kinetically.

Ø  Thermodynamic solubility can be defined as the concentration in solution of a compound in equilibrium with an excess of solid material at the end of the dissolution process and often considered as true solubility.

Ø  Kinetic solubility considers the precipitation after dilution in a suitable solution of a compound predissolved in a co-solvent or in aqueous media by pH adjustment for ionizable compound.

Solubility of drug in biorelevant dissolution media increased compared to the solubility in aqueous buffer because of enhanced wetting and micellar Solubilization.

 ·       Particle Size:

The dissolution rate is directly proportional to the surface area of the drug. Reducing particle size leads to an increase in the surface area exposed to the dissolution medium, resulting in a greater dissolution rate. Thus, the dissolution rate of poorly soluble drugs can often be enhanced markedly by undergoing size reduction (e.g., through micronization).

Particle size reduction does not always improve the dissolution rate. This is in part attributed to adsorption of air on the surface of hydrophobic drugs, which inhibits the wetting and hence reduces the effective surface area. In addition, fine particles tend to agglomerate in order to minimize the surface energy, which also leads to a decrease in the effective surface area for dissolution.

 ·       Drug pKa and gastrointestinal pH:

The amount of drug that exists in unionized form is a function of dissociation constant (pKa) of the drug and pH of the fluid at absorption sites. The relation between drug pKa and ionization and absorption is shown in Table 2.

Table 2: Relation between drug pKa and ionization

S.No	pKa range & drug nature	pH/site of absorption
1	Stronger acid  (pKa< 2.5)	Ionized at all pH values; Poorly absorbed from GIT.
2	Moderately weak acid  (pKa= 2.5- 7.5)	Unionized in gastric pH values and ionized in intestinal; better absorbed from stomach.
3	Very weak acid  (pKa >8)	Unionized at all pH values; absorbed along the entire length of GIT.
4	Stronger base  (pKa> 11)	Ionized all pH values; Poorly absorbed from GIT.
5	Moderately weak base  (pKa= 5-11)	Ionized at gastric pH; relatively unionized at intestinal pH; better absorbed from intestine.