dissolution-method development-ppt

Dissolution Method Developmentby

Bhanu Prakash . N

Analytical R&D(Formulations)

Email. Id: bhanu.analytical@gmail.com

Overview of Presentation

• Definition of dissolution

• Process of Dissolution for Solid Dosage Forms

• Theory of dissolution

• Various influencing parameters

• Regularotary Guidance

• Method Development(Chromatography and analysis)

• Key insights to investigations during sample Analysis.

Dissolution Definition

Dissolution is a process by which solid substance enters in the solvent

yield a solution.

Dissolution as a process

Tablets Disintegration Granules Deaggregation Fine Or Aggregates Particles Capsules Dissolution Drug in Solution

Wetting of the dosage forms

Penetration of the dosage from by the dissolution medium

Solid dosage form-- DT - Granules-disaggregation- fine partcles -- dissolution

Disintegration

Disaggregation of dosage form and dislodgment of the granules.

Dissolution

Occlusion of some particles of the Particle

Noyes whiteney equation for dissolution

dC D .A X (Cs-Cb) dt = h

Where dC/dt=Rate of drug dissolution at time “t”

D= diffusion coefficient of compound in the medium

A= surface area of the particle

h= Thickness of the stagnant film layer

Cs = saturated solubility of compound at the particle media interface

Cb = Concetration of compound in the bulk medium

Cb <<< Cs dependancy is only on Cs

Influencing Parameters - Wetting speed - surface tension- contact angle.

-Addition of surfactant - Air bubble trapping - Hydrophobic lubricant like talc, mg sterate in formulations

- For capsule gelation is hydrophilic

- Wetability of powder bed inside cap.

- Disaggregation -- compactability

- Tablets - pore volume is small- addition of disintegraters.-- strain and rupture.

Normally

Solutions > suspensions> capsules > tablets > coated tab

Instrinsic Dissolution

Instrinsic dissolution rate can be defined as rate of dissolution pure pharmaceutical

active when conditions such a pH , Surface area , Temparature, Agitation Rate and ionic strength of dissolution media kept

constant.

mg/cm2/min

Systematic Approach to Dissolution Method Developement

Litterature informationSBOA, PDR, PIL, pK data

Study the Drug Absorption characteristics.

• RLD’s.

•Classification.

•Tmax.

•Absolute bioavailability and

relative bioavailability.

•Food affect.

Solubility Study

What do we Get From Solubility Study ?

Rate Determining Step

Selection of Media For Dissolution Study

Type of Solubility

1) BCS-Highest Unit Dose in 250 ml of Dissolution media .

2) Saturated Solubility –Shake Flask method

BCS Guidance Summary

BCS takes into account three major factors that govern the rate and extent of drug absorption from IR solid oral dosage forms: solubility, intestinal permeability,

and dissolution.4 BCS classes are: 1 = HS, HP; 2 = LS, HP; 3 = HS,

LP; 4 = LS, LPDifferent formulations of rapidly dissolving BCS class 1 product can be given biowaiver if they show rapid and similar dissolution profiles over the physiological pH

range.BCS defines rapid dissolution, i.e., 85% in 30 minutes.

If dissolution is this rapid across the pH range, absorption not dissolution rate limited.

Solubility StudyMedia Selection :

0.1NHCl, 0.01 N HCl,

0.001 N HCl,

pH 2.1 SGF (fasted),

pH 3.0 SGF (fed)

pH 4.5 Acetate / Phosphate Buffer.

pH 6.8 Phosphate Buffer

pH 7.2 / 7.4 Phosphate Buffer

pH 6.8 Simulated intestinal fluid (fasted).

pH 5.0 Simulated Intestinal fluid(fed).

Solubility StudyMedia Selection :

If the drug is highly hydrophobic and insoluble,

• Buffers with Added surfactants can be used.

Note : Effect of surfactant shall be studied.– Not more than 1% is preferable,

– Beyond 2% shall be justified.– (look for alternate surfactants which gives

better dissolution with less concentration).

Solubility StudyMedia Selection :

• Based on solubility, The Media are selected for profile comparison.

• If the T max is Less than 2 hours : Acidic Media is preferred for the release testing.

• Look for discrimination in the relavant pH range.

• IF food affects bio-availability, then Simulated media study is very important.

• Use always pure grade of reagents for Simulated media preparation.

Sink conditionMinimum amount of drug to be dissolved

in order to select as a dissolution media.

3 times the unit dose is taken for study.

NLT 1.5 times the unit dose is the acceptance criteria.

First : at 25°C using API.

Next : at 37±0.5°C using API.

Next : at 25°C using API+Placebo (processed)

Next : at 37±0.5°C using API+Placebo (processed)

Next : at 37±0.5°C using drug Product (final formula)

Seven Steps to Become a Expert for Dissolution Method Development

Step-1Single Peak Chromatographic Method/UV scan

Successful Method Development

-No blank Inteferance

-No placebo Inteferance

-Peak Shape/ Tailing

-Shortest Run Time

-Major Degradant Seperation

Step-2

Standard Preparation optimization

(Knowledge of Solubility to be Used)

Step-3

Solution Stability in Dissolution Media

Step-4

Choice of Appratus- Paddle/Basket/Rpm/Volume/Time

Points for Profile

1) Appratus.

2) RPM-50/75/100

3) Volume –500/900/1000/2000/4000ml

4) Time points to get Discrimination

Step-4(conti.,)

Selection of Apparatus Widely used :

Apparatus 1 (basket)

Apparatus 2 (paddle)

Apparatus 3 (reciprocating cylinder)

Apparatus 4 (Flow through Apparatus)

Step-5

-Media Preparation

-Dissolved Oxygen/ Degassing of Media

-Temperature of Media

-Volume of media

-pH of Media

-Setting of Right Parameters for Auto Samplers.

-Use suitable sinkers or no sinkers.

Step-6

-Disintegration Pattern

-Floating Particle of Drug or excipients

-Heap Formation

-Cone Effect

-Type of Filters

-Sampling Errors

-Media Volume Measurements for ER

Step-7

Analysis of Samples

Successful Dissolution method Development and analysis Completes

Investigations– During Analysis of Samples

Possible errors :

•Media preparation.

•Standard preparation.

•Filters.

•Stability of solutions (std/test).

•Sampling / replacement.

•Interference (Chromatography/UV).

Investigations– During Analysis of Samples

•Always take additional sample at higher RPM ,10 minutes after the last time interval.

•Alternatively, Perform the assay of the residue

•Always record the physical observation and tablet to tablet variation.Involve Formulation scientist for physical observation.

•Verify and establish the role of sinkers.

•Measure the Volume of media at the end of the run for ER samples.

Investigations– During Analysis of Samples

• Clean the filters and lines thoroughly before starting the run.

•Verify the filters (compare with Manual sampling and centrifuge).

•Standard May absorb moisture. Preserve Properly. Check the validity dates and storage condition.

•Extra / additional peaks shall be investigated and the root cause shall be known.

•Observe peak distortions between standard and test.

Investigations– During Analysis of Samples

• If the drug is degrading, we shall also know what type of degradation it undergoes.

•Inject dissolution sample in RS method and find out if possible what is the degradant.

•Assess whether method is specific to the extent that it avoids interference.

•Are we stabilizing the solution or degrading further and stabilizing.

•Timing of stabilization is also very important.

Investigations– During Analysis of Samples

•Dissolution General chapter is harmonized Now.

Request For BiowaiverData Supporting :-Rapid and Similar DissolutionHigh PermeabilityHigh SolubilityBiowaiver: Class III compounds are eligible biowaiver if they dissolve within 15 minutes in buffer media pH 1.2 –6.8 (75 rpm)Biowaiver: Class II acids with D:S ratio < 250 ml at pH 6.8 and > 85 % dissolved within 30 minutes at pH 6.8 (75 rpm)

Thanks