SOP for Dose Solubility Volume Ratio of Active Pharmaceutical Ingredients

OBJECTIVE

The objective of this study is to demonstrate the solubility data and dose solubility volume ratio. 

SCOPE

This SOP is applicable to the procedure for performing solubility tests and its documentation. 

RESPONSIBILITY

• The QC executive is responsible for performing the solubility test analysis. 
• QC Manager is responsible for ensuring the implementation of SOP in solubility testing and its documentation. 

PROCEDURE

Solubility Data and Dose Solubility Volume:

• Criteria of Biopharmaceutics Classification System (BCS) system of APIs: 

1. Aqueous solubility 
2. Intestinal permeability 

• API classification according to BCS is shown in the below table

BCS Classification	Solubility	Permeability
BCS class I	High	High
BCS class II	Low	High
BCS class III	High	Low
BCS class IV	Low	Low

• Solubility: The solubility class boundary is based on the highest strength of an IR product that is the subject of a biowaiver request. A drug substance is considered highly soluble when the highest strength is soluble in 250 mL or less of aqueous media within the pH range of 1 - 6.8 at 37 ± 1°C. The volume estimate of 250 mL is derived from typical BE study protocols that prescribe the administration of a drug product to fasting human volunteers with a fluid-ounce glass of water. 

• The pH-solubility profile of the test drug substance should be determined at 37 ± 1°C in aqueous media with a pH of 1.2, pH 4.5, and pH 6.8. 

e.g., Highest Dose = 500mg, solubility (37°C) at pH 4.5 = 31.2 mg/mL 

DSV = 500/31.2 = 16.03 mL 

16.03mL < 250mL so highly soluble at pH 4.5 

Procedure:

• Transfer an accurately weighed sample according to its highest dose strength in the finished product, into a 250mL conical flask and add 250ml Standard buffer solution pH 1.2 and perform solubility at temperature 37 ± 1°C. 
• After adding the sample to the solvent immediately adjust the pH of the solution. 
• The buffer solution pH 1.2 should be heated at 37 ± 1°C using a magnetic stirrer provided with heat. Wait for 30 minutes. 
• The concentration of the drug substance in pH 1.2 should be determined using a validated assay method. 
• Solution pH also measures at the end of the equilibrium solubility study. 
• Repeat the same process mentioned above using USP acetate buffer pH 4.5 and USP phosphate buffer pH 6.8. 

REFERENCES

• Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System. Guidance for Industry. U.S. Department of Health and Human Services. Food and Drug Administration. 

• WORLD HEALTH ORGANIZATION. Proposal to waive in vivo bioequivalence requirements for the WHO model list of essential medicines immediate release, solid oral dosage forms. Geneva: WHO, 2005. 

ABBREVIATIONS

BCS – Biopharmaceutics Classification System 

API - Active Pharmaceutical Ingredients 

DSV – Dose Solubility Volume 

ANNEXURE

Nil

REVISION HISTORY

Nil

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