Dissolution

Basics of dissolution

1. WHY Dissolution ? K. Vignesh, M.S. (Pharm)

2. Dissolution Dissolution – Mass transfer of solid substance from the solid surface to the liquid phase. It is a dynamic process Solubility – Maximum amount of solute dissolved in given solvent. It is a static (lack of movement) process Dissolution rate - rate at which the drug released from dosage form under standardized conditions of liquid-solid interface, temperature and media composition The actual drug release in the human body can be measured  in-vivo  by measuring the plasma or urine concentrations in the patient. Due to impracticalities involved in employing such techniques on a routine basis, leads to the introduction of official  in-vitro  dissolution tests and its principle function involves, Optimization of therapeutic effectiveness during product development and stability assessment. Routine assessment of production quality to ensure uniformity between production lots. Assessment of ‘bioequivalence’. Prediction of  in-vivo  availability, i.e. bioavailability. Active ingredient is released in the predicted way https://www.labhut.com/education-centre/about-dissolution-testing/dissolution-testing-education.html

3. Factors affecting dissolution Test apparatus : Design, size, shape of the container, Nature and speed of agitation, Performance precision of the apparatus. Process : Method of dosage form introduction, Sampling technique, Changing the dissolution medium. Dissolution medium : Medium types, Viscosity, Volume, Temperature, Sink/non sink condition.

4. Need of stirrer Reason for Shear (RPM) – Helps in maintain contact between the surface of the drug (solid/liquid) after disintegration(solid dosage form) and the rate at which fresh solvent contacts it. This mimic the in vivo GI movement’s. For Example: Tablet particle after disintegration suspended in dissolution media without agitation makes the dissolution medium immediately around the tablet particle would become saturated and dissolution would essentially stopped due to saturation of medium i.e., no fresh medium to dissolve further drug molecules. When, media starts to move as a result of shear the saturated film is ‘washed’ away and new media enables the dissolution to continue again. Flow pattern variables, turbulence, viscosity, surface tension and dissolved gasses affects Shear. For USP Apparatus I – 50 to100 rpm; USP Apparatus II – 50 to 75 rpm agitation are commonly used Suspension – 25 and 50 rpm are acceptable

5. Sink Condition The main aim of the sink condition was to maintain concentration that should never be close to the saturation point, if not, the dissolution rate of drug under dissolution would be slowed and the data would cease to be reproducible. Typically 5 to 10 times greater volume of dissolution media is used in respect to that saturation point of drug during dissolution to ensure that sufficient media is present in for drug to be dissolved to ensure un-impaired dissolution, called “freely soluble” or “sink condition”. (OR) The sink condition may be defined as the volume of dissolution medium, with or without a solubilizer, needed to provide complete dissolution of the expected amount of drug present in the product. The only requirement for a sink condition is that the volume of the medium should be such that it would provide complete dissolution of the expected amount of the drug. Generally uses 10 to 15% volume than the volume of the medium (with or without solubilizer) required to dissolve the expected amount of the drug. More elaborately, Sink condition is the ability of the dissolution media to dissolve at least 3 times the amount of drug that is in your dosage form. This is the reason dissolution volume 900/1000mL are used, while 500mL or below may be used when measurable level of the drug is lower or low dose oral and non oral delivery and implantable devices levels. It uses mini vessel ( minipaddle and baskets) in volumes as low as 100mL or 200mL or 300mL, and higher volumes like 2000ml vessels are fairly standard and some more exotic options like 4L and 5L have been used. http://www.drug-dissolution-testing.com/?p=1479

6. Cont., The magic number ‘’3’’ comes out of the Noyes-Whitney equation, - Where, - Saturation constant of API ; - API concentration at time t. Effects : a) Meeting sink condition - - would be (3 - 0) at beginning of dissolution, - would be (3 – 1 or 2) at end of dissolution, so dissolution rate would be slowed by only 1/3 due to dissolved drug; b) Fail to meet sink condition – in vivo performance would not match. While dissolution closer the concentration of API get to saturation, the slower the dissolution rate. Because in a human body typically drug product would not get saturation anywhere (As we are eating and drinking throughout the day), so we do not experience this slowing of dissolution rate.  

7. Why 900mL ? Reason – A) Biological, B) Matter of convenience A) Biological – Human stomach holds about 1L in fed condition as average person when having medicine with their meal. The volume of the stomach is quite variable depend on condition like fasten, fed or overfed state ranging from very low 75 mL and can go up to around 4L in some overfed individuals. B) Convenience – 1L organic chemistry reaction flask with simple stirrer were initially used as dissolution apparatus , prior to USP/BP/IP/EP apparatus which we use today. Now, the volume was lowered to 900mL to account for volume displacement from the product and stirring shaft. So that the dissolution medium in vessel does not spill over during the dissolution.

8. Small volume dissolution Useful technique when dosage form only contain microgram or nanogram levels of API, or for extended release profile or high potency dosage forms where small amounts are released and may be difficult to detect using HPLC or UV-Vis. USP Official: Test media – Volume of 500mL to 4000mL - Standard USP 1&2 (Poorly soluble dosage form) dissolution apparatus. Test media – Volume of 150 mL to 300mL - Standard USP 3 (Biorelevant dissolution) dissolution apparatus Test media – Volume of less than 100mL - Standard USP 4 (Simulated gastrointestinal condition) dissolution apparatus Test media – Volume of 500mL to 100mL - Standard USP 5 and 6 (Transdermal system) dissolution apparatus Test media – Volume of 50 mL to 400mL - USP 7 (Small transdermal patches) dissolution apparatus [Specific vessel size not in USP] Small Volume ( No USP official specification): Test media – Volume of 300mL, 200mL, 100mL (30mL minimum holding capacity) -  Mini paddles or baskets dissolution apparatus Test media – Volume of 100mL (50mL minimum holding capacity) – Scale down reciprocating dissolution apparatus Test media – Volume of less than 15mL – Small volume USP 4 dissolution apparatus USP 5 and 6 - NA Test media – Volume of as low as 5mL - USP7. http://dissolutiontech.com/DTresour/200902Articles/DT200902_A03.pdf

9. CONT., Small volume (Official) Test media – Volume of 150 mL - Mini paddles or baskets dissolution apparatus (USP form Chapter 40(6) – in 2014) Test media – Volume of 250 mL – Chinese small volume mini spin paddle dissolution apparatus Non – USP apparatus: Test media – Volume of less than 150mL (3mL minimum holding capacity) - Rotating bottle dissolution apparatus [NF 1975]

10. Media selection Based on solubility in media for pH profile comparison and evaluate influence of buffer, surfactant on solubility and stability of the drug substance. T max is less than 2 hours – Acidic media is preferred (Gastric) Food effect on bioavailability – Study on simulated or biorelevant media. Hydrophobic/ insoluble drug – Surfactants are added (N.M.T 1% is preferable, beyond 2% should be justified) Sink condition : 3 times the unit dose is taken for study and NLT 1.5 times unit dose is the acceptance criteria. The dissolution selection involves,

11. Dissolution Vessels Size of Vessel   Typical Use Made of 4 Litre Sample Pooling, Veterniary Applications Clear glass vessel Amber glass vessel Clear plastic vessel * ( PTFE coated glass vessels) Amber plastic vessel Precision vessel – high geometrical precision of curvature and the inner surface of dissolution vessels with standard ASTM calibration.  Peak Vessels - have a small peak at the bottom of the vessel designed to prevent cone formation a 2 Litre Low Solubility Drugs 1 Litre 1000ml, 900ml and 500ml Tests 500ml 500 ml Tests 300ml Low Dosage Forms Requires special paddles  200ml 100ml * Used where the dosage form will stick to a glass vessel and water bath has to be set higher than normal to achieve 37°C due to poor thermal qualities a http://www.dissolutiontech.com/DTresour/1996Articles/DT199605_A02.pdf USP : 1L Vessel ; Height: 160-210mm; OD: 98-106mm; Hemispherical Bottom 

12. Media specifications Deliver Media volume - Media should be the correct volume within 1% (all volumes are measured at 20-25 degrees), and dispensed into the dissolution vessel. Temperature - The temperature of the media should be 37 o C +/- 0.5 o C. Note that the actual water bath temperature may need to be set above 37 o C in order to achieve the correct temperature inside the vessels and lowering the baskets into the media will temporarily decrease the media temperature. So, need to ensure that all vessels are actually at 37 o C before the test begins and not lower. Introduction of Dosage Forms – a) Basket - in the clean, dry baskets using forceps or gloves and dosage form should not have been left on the open bench prior introduction ; b) Paddle - sample is introduced with the paddle stationary because, there is a good chance that it will collide with the blade, and tablet will not fall to the bottom of the vessel, but to one side particularly in coated or sticky tablets Starting test - a) Basket - start the test when basket lowers into the media by without leaving the dosage forms in the baskets for an extended period; b) Paddle - start the test when sample lowers into the media.

13. How air bubbles formed? Presence of air, or gas, in the dissolution medium causes the variability in dissolution results. Bubble formation: Drug dissolution tests are conducted using dissolution media maintained at 37 °C, however, media used are generally stored at room temperature around 20 °C before performing dissolution study. Therefore, change in solubility of the dissolved gasses in dissolution media, from higher to lower solubility on heating up to 37 °C, causes the dissolved gasses to come out of the medium in the form of tiny bubbles which tend to stick at random to the vessel and spindle surface, and may be to the product itself. once the medium is equilibrated at 37 °C the formation of the bubbles stops. Prevention: a) Application of Vacuum; b)Remove the temperature gradient effect, i.e., avoid transferring low temperature medium directly into the dissolution vessels; c) Filtration. Note : Media containing surfactant is not deaerated due to excessive foaming. http://www.drug-dissolution-testing.com/?p=1485

14. Sampling in dissolution According to USP, 'Within the time interval specified, or at each of the times stated, withdraw a specimen from a zone midway between the surface of the Dissolution Medium and the top of the rotating basket or blade, not less than 1cm from the vessel wall’ Example: 500mL dissolution media, the distance between the top of the paddle/ a little lower than the top of the basket and the surface of dissolution medium is about 1 inch away from the vessel wall to ensure that the media is free flowing. Not recommended to sample close to shaft due to poor hydrodynamics. Different sampling position lead to errors with readings since the concentration cannot be assumed to be linear throughout the vessel. Samples should be taken at the allotted time within a ±2% time window or 15 minutes. After sampling a small amount of sample should be gently back-flushed back into the vessel to avoid turbulence but to wash off any particles from the filter surface.

15. Dissolution Filter Aim is to trap particle from dosage form during sampling and preventing from generating false results. Also called as ‘‘Cannula Filters, PoroPlast Filters, Full Flow Filters, Depth Filters or simply Dissolution Filters’’ Manufactured from porous Polyethylene or porous PVDF and typically diameter of filters will be 1/16" or 1/8"  Filter Porosity - 1µm up to 70µm porosity ; high porodity - un-dissolved particles will pass through the filter and affect the results ; Low porosity - the flow rate may not be sufficient and cavitation can occur. To check passage of particle - test the concentration immediately, and again after shaking the sample for a suitable amount of time to ensure any particles have been dissolved and check for concentration. Filter Adsorption – API have a chance to adsorbed onto the filter material itself. Can be identified by simply filter some standard solution to check if the concentration is reduced against the unfiltered standard Contamination from Filters – Found by taking an aliquot of blank media, measure that, and then push through the filter and measure again.

16. CONT., Cannula filter – used when high levels of particulate are present Filter disc – Designed to keep filtration process outside the vessel and used as a in-line filter in low volume sample probes Filter tips – fitted on the end of larger diameter sample probes and usually smaller than cannula filter.

17. Sampling with Cannula Sampling Cannula usually fitted with a filter on the end and made from either stainless steel or PEEK so that they do not adsorb or interfere with the active ingredient Use of resident probes/cannula which stay in the dissolution vessel all the time should have diameter small enough, not to affect the hydrodynamics in any way, and the use of filters inside the vessel must be avoided. Cannula vary in length from 4.75” (120mm) to 15” (380mm) as the midzone will change with the volume.

18. Selection of dissolution apparatus Based on Formulation design and practical aspects of dosage form performance in the in vitro dissolution.

19. Apparatus 1 - The Rotating Basket First official method adopted in 1970. The standard basket consists of a stainless steel 40 mesh (40 openings per linear inch of mesh), but many variations depending on the monograph and application like 10,20,100,150 meshes and suppository baskets manufactured from PTFE with vertical slits are used. Basket are coated with PTFE or an inert substance such as gold or titanium to prevent reaction with the dosage form and have a small vent hole of 2.0mm at the top to allow air to escape from the basket. Never introduce a dosage form into a wet basket

20. problems associated with the rotating basket test Clogging - incorrect mesh size, blockage because of gummy excipients (other ingredients which make up the tablet), fast particulate release from the tablet, and air bubbles Air Bubbles - When a basket is lowered into the media, there is a danger that air bubbles can be trapped inside, or under the basket. The small hole in the basket hub is supposed to release air trapped inside but that does not always happen. Bubble trapped in (dosage form in the basket can float to the bubble) or under the basket (prevent media movement through the mesh) prevents dissolution. Low Media Agitation - generate remarkably little media movement, particularly at low RPM makes the disintegrating tablet, particles to clump together at the bottom of the media forming cone. Sampling Sensitivity - Correct and reproducible sample position is important because at low media agitation, there is the potential for concentration gradients of active ingredient to be built up in the vessel.

21. Apparatus 2 - Rotating Paddle Originally developed by Poole (1969) and was refined by scientists at the FDA for Drug Analysis in St Louis and most widely used method in dissolution testing. As per USP, Polyfluorocarbon coating is used to reduce the interaction between steel and the dosage form. But, Polyfluorocarbon coating is a high temperature process and is difficult to gain a consistent thickness over the paddle. Poor coating and handling leads to flaking of the coating and disrupt the flow. Alternatively solid PTFE made paddles are used with same dimensions as the steel paddles specified by the USP.

22. Capsule and Tablet Sinkers Dissolution reproducibility will be severely restricted if the dosage form is not in the same position in the vessel for each test. Floating dosage forms can present a real problem and may be weighted with a sinker which should be heavy enough to cause it to sink to the bottom of the vessel and also for dosage forms like film coated tablet sticking to the walls of the vessels. As per USP sinker is defined as, ‘‘ A small, loose piece of non-reactive material, such as not more than a few turns of wire helix, may be attached to dosage units that would otherwise float’’ The sinker should have minimal surface contact with the dosage form as this can affect the dissolution rate Sinkers are made from 316 stainless steel and are resistant to water or standard dissolution media;  PTFE Coated Sinkers can also be used with magnetic retrieval systems, or where there may be a reaction or adsorption between steel and the tablet; Plastic coated  “3 Pronged sinkers’’ can also be useful where tablets may stick to the sides of the vessel. Incorrect sinker selection can result in the wire occluding the surface of the dosage form thus restricting the free flow of media over the surface and reducing the dissolution rate

23. Cont., Sinker type Style Material Coating Capsule size Basket (coin shaped dosage forms) Japanese Basket, Basket – 8,10,40 Mesh. 316 S.S. - 000, 1, 2, Pronged 3 Prong 316 S.S., Nylon / P.P. - 1, 2 O-Ring O-Ring 316 S.S. - 1 Spiral (sticky tablets) Butterfly, ' Sotax Style’ Helix, Strip film 316 S.S., Music Wire PTFE 000, 0, 2, 3, 5, veterinary applications Wire Sinker Wire 50' 316 S.S. - - https://www.labhut.com/education-centre/dissolution-accessories/sinker-selection-guide.html

24. Crescent-Shaped Spindle Drug dissolution testing using paddle and basket spindles face many hurdles in obtaining relevant and reproducible results, poor product-medium interactions, potential sensitivities to vibration, air/gases content in media, positions of product in vessels, uneven mixing patterns, variation in vessel dimension even within specifications. Crescent-shaped spindle can easily be installed in the vessel-based dissolution apparatuses (basket and paddle) to provide a product-independent dissolution testing approach for improved drug dissolution assessments Crescent-Shaped Spindle - repeatability and reproducibility, crescent shape spindle moves the product around at the bottom of the vessel and forces the product and/or its aggregates to move to provide product/medium interactions, No unstirred and stagnant areas, free from “cone” formation and/or positioning effects of the product, not require product dependent methods, product independent testing to reflect true dissolution characteristics, Small amounts of solubilizer for low aqueous solubility drug, Does not require de-aeration of the medium, testing is free from sensitivities of usual and expected vibrations and variations in vessel/spindle alignments, http://dissolutiontech.com/DTresour/200411Articles/DT200411_A02.pdf http://www.drug-dissolution-testing.com/blog/files/cssadvantages.pdf

25. Software Dose, Disintegration and Dissolution Plus ( DDDPlus ) - simulates the in vitro dissolution of API and formulation excipients in various dosage forms under various experimental conditions. http://dissolutiontech.com/issues/202005/DT202005_A01.pdf

26. Vendors SOTAX (USA) Agilent Technologies (USA) Distek , Inc. (USA) Teledyne Instruments (USA) Pion Inc. (USA) ELECTROLAB INDIA (India) Electronics India (India) LAB INDIA (India) Panomex Inc.(India) ERWEKA GmbH (GERMANY) Pharma Test Apparatebau AG (GERMANY) BIOBASE (Jinan, China) Hannox International Corporation (TAIWAN) Ethik Technologies (São Paulo, Brazil)

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