SEMINAR ON…. In Vitro Dissolution Testing Models Presented by : Saiesh P.Phaldesai 1st year M.Pharm Dept. of pharmaceutics Srinivas college of pharmacy Mangalore

CONTENTS Introduction. Need for dissolution testing. In vitro dissolution testing models. In vitro - In vivo correlation. References.

NEED FOR DISSOLUTION TESTING Evaluation of Bio availability. Development of more efficacious and therapeutically optimal dosage forms. Minimizes use of humans as test subjects Ensures quality of the product Correlation between dissolution results & bioavailability of product between batches. Product development, quality control and research and application. Screening of formulations during product development .

Official dissolution rate test apparatus App no IP BP USP 1 Paddle Basket Rotating basket 2 3 Flow through cell Reciprocating cylinder 4 Flow through cell 5 Paddle over disk 6 Rotating cylinder 7 Reciprocating disk

Name of Apparatus Drug Product Rotating basket Tablets Paddle Tablets, Capsules, Modified release products, Suspensions Reciprocating Cylinder Extended release drug products Flow cell Low water soluble drugs Paddle over disk Transdermal drug products Cylinder Reciprocating disk Rotating disk (non USP –NF) Extended realese drug products(Beads)

INVITRO DISSOLUTION TESTING. Rotating basket method. Cylindrical basket of 22mesh. Rotating speed-100 rpm. As per IP height of dissolution jar is 168+8 mm and internal diameter is 102+4 mm and height of basket 36.8+3 mm and diameter is 25.4+3 mm Temp. maintained at 37 ̇ c Calibration tablets of Prednisone-for disintegrating tablets. Salicylic acid calibration tablets-for non disintegrating tablets. For capsules & dosage forms that tend to float.

2) Paddle method. Teflon coated paddle to minimizes turbulence due to stirring. Vertically attached. As per IP diameter of the paddle is 74.5+0.5 mm Position & alignment of the paddle are specified in USP same set of standards for calibration. Temp at 37 ۠c. Very sensitive to tilting. 2 - 50 rpm-for solid oral dosage forms, 25 rpm-suspensions. For tablets, capsules, suspensions. Few turns of platinum wire as a Sinker .

3) Reciprocating cylinder method. Set of cylindrical, flat –bottomed glass vessels equipped with reciprocating cylinders For testing of extended release products and for beads. temp. 37۠ c.

4) Flow through cell method Reservoir of medium Pump that forcing medium through the cell holding test sample Flow rate from 4 to 16 mL/min. For modified release dosage forms, containing active ingredients with limited solubility. Laminar flow by pulse less pump Dissolution medium may be fresh or recirculated Fresh medium ,dissolution rate at any moment can be obtained.

Flow through cell

5) Paddle over disk method Sample holder or disk assembly that holds the product. Temperature -32oC. Paddle is placed over the disk assembly. Sample drawn midway between the surface of the dissolution medium and the top of the paddle blade. For testing the release of drug from transdermal products.

6) Rotating cylinder method A stainless steel cylinder is used to hold the sample. Sample is mounted on to cuprophan. Temperature 32oC. For testing transdermal preparations. 7) Reciprocating disk method A motor drive assembly is used to reciprocate the system vertically. Samples are placed on disk shaped holders using cuprophan supports Reciprocating frequency is about 30cylces per minute.

Advantages of official methods Better reproducibility For capsules as they tend to float at surface thus minimizing area exposed to dissolution fluid

Disadvantage Clogging of basket screen by gummy particles Tendency of a light particles to float at surface after leaving baskets or in paddle method Sensitivity of apparatus to variables such as vibrations, eccentricity. Rapid corrosion of SS mesh in presence of HCl Sensitivity of apparatus to any slight changes in paddle orientation Non reproducible position of tablet at bottom of flask

Dissolution acceptance: stage Number tested Acceptance criteria S1 6 Each unit is not less than D+5% S2 average of a 12 units(S1+ S2) is equal to or greater than D and no unit is less than D+15% S3 12 Average of 24 units (S1+ S2+ S3) is equal to or greater than D not more than 2 units are less than D +15% and no unit is less than D +25% where D is amount of dissolve active ingredients expressed in % in individual monograph

Non official methods Tumbling method Rotating disk method Rotating bottle method Intrinsic dissolution method Peristalsis method Sartorius apparatus Beaker method Dialysis method

Tumbling method Rotating disk method In this method dosage form is placed in tubes or bottles which are rotated using revolving drum Rotating disk method Developed by late eino nelson and described by Levy and Sahli. Non disintegrating tablets or discs mounted in plexiglas holder, one surface exposed to the dissolution medium Holder is attached to the metal shaft ,free from vibration The tablet immersed one inch below the surface of 200 ml of dissolution fluid , temp 37 ۠c , in 500 ml three nacked round bottom flask , rate is 550 rpm. Samples were taken and assayed for drug content.

Rotating filter method It consists of magnetically driven rotating filter assembly and a 12 mesh wire cloth basket in which dosage form is placed The sample is withdrawn through spinning filter for analysis Sartorius apparatus It utilize in vivo stimulative method The absorption stimulater stimulates passive drug transport process that occur in vivo from GIT tract to plasma across lipoidal mucosal barrier

Intrinsic dissolution method Rotating bottle method It consists of rotating rack to hold sample drug products in bottles and they are capped tightly rotated in 370c temperature bath Sample are decanted through a 40 mesh screen and residue are assayed. Intrinsic dissolution method Most method for dissolution deal with finished drug product The dissolution of drug powder by maintaining constant surface area is called intrinsic dissolution. It is expressed as mg/cm2 /min.

Peristalsis method To stimulate hydrodynamic condition of GIT tract in an in vitro dissolution device. It consists of rigid plastic cylindrical tubing fitted with septum and rubber stopper at both ends. Dissolution chamber consist of a space between the septum and the lower stopper Dissolution medium pumped with peristaltic action through the dosage form

Beaker method Reported by Levy and Hayes(1960) Dissolution medium , 250 ml of 0.1 N HCl at 37۠ c placed in a 400 ml beaker Agitation by three blade polyethylene stirrer,5 cm diameter and rotates at 60 rpm. Stirrer immersed to a depth of 2.7 cm in medium and in the center Samples are removed and assayed for the content.

Dialysis methods Cell consist of 32 mm inflated membrane Plugged at the lower end by tight fitting cylindrical perspex box. Upper end of the tube held by thin perspex ring inserted into the tube and secured by an elastic band The cell , suspended from the arm of a tablet disintegration apparatus and containing the dosage form in 50 ml of distilled water at 37 ۠ c

The cell was raised and lowered 30 times a min into 150 ml of distilled water at same temp. Agitation by slight flexing and streching of the dialysis membrane as it enters and leave the bath Rotation at 60 rpm Samples taken and assayed for content.

INVITRO-INVIVO CO-RELLATION The FDA regulations of 1977 on bioavailability and bioequivalence stated that dissolution test, the preferred in-vitro test should be co-related with the in vivo data. Biopharmaceutics drug classification system. Theoretical basis for correlation. JW= PWCW JW Drug flux through intestinal wall at any position & time PW permeability of the membrane CW drug concentration at the intestinal membrane surface

DISSOLUTION RATE Vs ABSORPTION RATE Absorption time - In correlating dissolution data to absorption data It refers to the time for a constant amount of drug to be absorbed Correlation between time required for a given drug to be absorbed &time required for the same amount of drug to be dissolved in vitro for three sustained release aspirin products. The results from this study demonstrated that aspirin was rapidly absorbed and was very much dependent on the dissolution rate for absorption.

PERCENT OF DRUG DISSOLVED Vs PERCENT OF DRUG ABSORBED One must consider Appropriate dissolution medium Slow dissolution stirring rate An example of continuous in vitro-in vivo correlation of aspirin

MAXIMUM PLASMA CONCENTRATIONS Vs PERCENT OF DRUG DISSOLVED IN-VITRO Different drug formulations Poorly formulated drugs-incomplete dissolution, release –lower plasma drug concentration Peak drug serum concentration is higher for the drug product that shows the highest percent of drug dissolved

In-vitro in-vivo correlation for 100mg Phenytoin sodium capsule is shown the graph

SERUM DRUG CONCENTRATION Vs PERCENT OF DRUG DISSOLVED Simulated gastric juice In vivo in vitro correlation between10 minute serum level and dissolved at 1.2 minutes (o) & the 20 minute serum level and percent dissolved 4.2 minutes (●)

REFERENCES Dissolution, bioavailability & bioequivalence by, Hameed M. Abdou. Biopharmaceutics & clinical pharmacokinetics by, Milo Gibaldi. Applied Biopharmaceutics & clinical pharmacokinetics by, Leon Shargel /Andrew B. C. Yu Pharmaceutical dissolution testing by, Banker, Dekker series. Biopharmaceutics & pharmacokinetics by, G.R. Chatwal. Biopharmaceutics & pharmacokinetics – A treatise D.M.Brahmankar, Sunil B. Jaiswal. www.google.com

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