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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 for the procedure to perform solubility test and its documentation. 

RESPONSIBILITY:
  • QC executive is responsible to perform solubility test analysis. 
  • QC Manager is responsible to ensure 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: 
          a. Aqueous solubility 
          b. Intestinal permeability 
  • API classification according to BCS as shown in 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 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 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 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 sample to the solvent immediately adjust pH of solution. 
  • The buffer solution pH 1.2 should heat at 37 ± 1°C using magnetic stirrer provides 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 measure 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 

REVISION HISTORY: 
Nil

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