INTRODUCTION:

The Dissolution rate may be defined as amount the of drug substance that goes in the solution per unit time under standard conditions of liquid /solid interfaces, temperature and solvent composition. It can be considered as a specific type of certain heterogeneous reaction in which a mass transfer result as a net effect between interruption and deposition of solute molecules at a solid surface¹. Dissolution is a process in which a solid substance solubilises in a given solvent. i.e., mass transfer from the solid surface to the liquid phase².

The processes involved in dissolution of solid dosage form:

Fig 1: Schematic illustration of dissolution process of solid dosage forms.

Importance And Applications Dissolution Test:

Importance:

Result from in-vitro dissolution rate experiments can be used to explain the observed differences in in-vivo availability.

· Dissolution testing provides the means to evaluate critical parameters such as adequate bioavailability and provides information necessary to formulator in development of more effective and therapeutically optimal dosage forms.

· Most sensitive and dependable predictors of in-vivo availability³.

· Dissolution is examination of pharmaceutical dosage forms has appeared as single most important test that will ensure the quality of product².

· It can ensure bioavailability of product between batches that match dissolution criteria.

· Secure batch-to-batch quality equivalence both in-vitro and in-vivo, but also to screen formulations during product development to occurs at optimally effective products.

· Physicochemical properties of model can be understood needed to resemble in-vivo environment.

· Such models can be used to display potential drug and their associated formulations for dissolution and absorption characteristics⁴.

· Serve as standard quality control procedures, once the form of drugs and its formulation have been finalized⁵.

Application:

Product Development:

Important tool development of dosage form. Support in guiding the selection of illustration formulations and for determining optimum level of ingredients to achieve drug release profiles. Especially for extended-release formulations⁶.

Quality assurance dissolution test:

Dissolution test performed on subsequent production lots and is used to check the lot-to-lot performance characteristics of drug product and provide continued assurance of product integrity⁷.

Comparability Assessment:

Also useful for evaluation the impact for pre-or-post-approved changes to drug products such as changes to formulation or manufacturing process. Thus In-vitro Comparability Assessment is critical to assure continued performance identically and product affinity⁸.

Waivers of In-vivo Bioequivalence Requirements:

In-vitro dissolution testing or drug release testing may be used for look up waiver of required product to conduct in-vivo bioavailability or bioequivalence studies⁹.

Product Stability:

Product stability In-vitro dissolution also used to evaluate drug product quality with aspect to stability and shelf-life. As product age, physicochemical parameter changes to the dosages form may alter dissolution characteristics of drug product with over time¹⁰.

Factor Affecting Drug Dissolution and Dissolution Rate:

Physicochemical properties of the drug:

Solubility of drug plays a main role in controlling its dissolution from dosage form. Aqueous solubility of drug is an important factor that determines its dissolution rate. Minimum aqueous solubility of 1% is required to ignore potential solubility limited absorption problem. Studies of 45 compounds of different chemical group and a wide range of solubility disclosed that initial dissolution rate of these substance is directly proportional to their respective solubility¹¹.

a) Salt formation:

· It is one of the most common approaches used to grow on drug solubility and dissolution rate. It has always been supposed that sodium salts dissolve faster than their corresponding insoluble acids.

· Ultimate drugs are either weak acids or weak bases. A once of the easiest approaches to enhance the solubility and dissolution rate to enhance the solubility and dissolution rate of such drugs is convert them into their salt forms¹².

b) Particle size:

· There is a direct relationship between surface area of drug and its dissolution rate. It is clear that larger the surface area, higher dissolution rate. Since the surface area increase with decreasing particle size, a decreasing in particle size, which can be expert by micronisation higher dissolution rates may be achieve through depletion of particle size.

· When micronisation reduces the size of particles below 0.1 microns that there is an increase in the intrinsic solubility and dissolution rate of the drug¹³.

· In hydrophobic drugs like aspirin Phenacetin and Phenobarbital, micronisation actually results in the effective surface area of such powder and thus, a thus, a fall in the dissolution rate¹⁴.

c) Solid state characteristics:

· Solid state characteristics of drug, such as amorphicity, consistency, state of humidity and polymorphic structures have signification influence on dissolution rate¹⁵.

· Amorphous forms of drug maintain to dissolve faster than crystalline materials. E.g. Griseofulvin.

d) Co-precipitation:

· once or convert spherical granules into a disc shaped particle with a large increase in the effective surface area. This condition is an increase in the dissolution rate of the tablet.

· Dissolution rate of pure drug can be changed significantly when mixed with various additions during manufacturing process such as diluents, binders, dyes, granulating agents, lubricants and disintegrats.

· Generally similar tablet or capsules displayed differences in their dissolution rate of their active ingredients¹⁶.

Processing Factors:

a) Compression factors:

· The compression force working in the process influence density, hardness, disintegration test and dissolution of tablets.

· In the first condition, higher compression force increase the density and hardness of tablet, decrease porosity and hence penetrability of the solvent into the tablet, retard’s wet ability by forming a hard and more effective sealing layer by the lubricant, and in many cases, promotes compact bonding between the particles, all of which result in slowing of the dissolution rate of tablets¹⁷.

· In the 2^nd condition, higher compression forces cause distortion, crushing or breaking of drug particles into smaller identical tablet or capsules exhibited differences in their dissolution rates of their active ingredients¹⁸.

b) Method of granulation:

· The granulation process in generally increase dissolution rate of poorly soluble drug.

· The wet granulation process is the conventional technique. But deviation is the dissolution profile of sodium salicylate tablets prepared both method wet granulation and direct compression where the was found more complete and faster rate¹⁹.

· A recent method is called as “Agglomerative phase of communication (APOC) was found to produce were stronger tablets and rapid dissolution rate than those made up by wet granulation. The viable mechanism is increase internal surface area of the granules prepared by APOC method²⁰.

c) Drug excipient interaction:

· This interactivity such as any unit operation such as milling, mixing, blending, drying and granulation result change in dissolution.

d) Storage Condition:

· The storage condition of dissolution rate of Hydrochlorothiazide tablets granulated with acacia displayed decrease in dissolution rate during 1year of aging at room temperature.

Factor Relating Dissolution Test Apparatus:

a) Agitation:

· The agitation thickness of the diffusion layer is inversely proportional to the agitation speed and these conditions can markedly affect diffusion-controlled dissolution²¹.

· Agitation intensity and rate of dissolution varies considerably to type of agitation used, degree of laminar and turbulent flow in system, shape and design of stirrer.

· The speed of agitation flow that continuously changes the liquid or solid interface between solvent and drug²².

· Thus, in general relatively low agitation should be applied.

1) Paddle Method-50-75rpm

2) Basket Method -100rpm

b) Stirring Element Alignment:

· The USP state that the axis of the stirring element not deviate more than 0.2mm vessel, which defines centering of the stirring shaft to within ±2mm

· Test using paddle apparatus suggest that tilt in excess of 1.50 may increase dissolution rates from 2to 25%.

c) Sampling Probe Position and Filter:

· The sampling probe can influence the hydrodynamic of the system and so that change in dissolution rate.

· For sampling position of the USP\NF states that sample should be separated approximately half the distance from the basket or paddle to the basket or paddle to the dissolution medium and not closer than1cm to side of the flask²³.

Drug Product Formulation factor:

a) The dissolution rate:

· Diluents are commonly added in tablet and capsules influence the dissolution rate of drug.

· The organic diluents, carbohydrates are used for examples: starch, lactose and microcrystalline cellulose.

· Different types of drug administration used affect classify of different varieties of starch used in the starch in order was potato starch>corn starch>arrow root starch>rice starch²⁴.

b) Disintegrants:

· Disintegrating agents before and after the granulation added affects the dissolution rate.

· Microcrystalline cellulose is a good disintegrating agent but compression force is high, it may change drug dissolution.

· Starch is not an excellent diluent but also high-level disintegrant due to its hydrophilicity and swelling property²⁵.

c) Binder and Granulating Agents:

· These materials are used to hold powders together to form granules or promote cohesive compacts for directly compressible materials and tablet remains intact after compression.

· Large amounts of such binders increase hardness decrease disintegration and dissolution rates of tablets.

· Used commonly binders like starch, cellulose derivatives, acacia, PVP, etc. other include gelatin and sugar solution²⁶.

d) Lubricants:

· They increase the dissolution rate of poorly soluble drug. This is due to the lowering of interfacial tension increase effective surface area which in turn results in faster dissolution rate.

· E.g.: Non ionic surfactant lysolecithin increase dissolution rate of phenacetin granules²⁷.

e) Water Soluble Dyes:

· The dissolution rate of single crystal of sulphathoazole was found to decrease differently in presence of FD/C Blue No1. Their are inhibit the micellar solublization effect of bile salt on drug.

· Cationic dyes are more reactive than the anionic ones due to their greater power for absorption²⁸.

Factors Relating Dissolution Test Parameter:

a) Temperature:

· The drug solubility is temperature dependent therefore careful temperature control during dissolution process is especially important.

· Generally, a temperature of 37º±0.5is maintained during dissolution determination of orally dosage forms and suppositories.

· For the topical preparation’s temperature as low as 30ºand 25º have been used²⁹.

b) Dissolution Medium:

· The dissolution medium it is very important factors affecting and is itself affected by number of factors such as:

i) Effect of PH

ii) Volume of Dissolution Medium and Sink Condition

iii) Deaeration of Dissolution Medium

Theories of Dissolution:

There are three dissolution theories:

1) Diffusion layer model/film theory

2) Danckwert’s model/penetration or surface renewal theory.

3) Interfacial barrier model/Double barrier or limited solution theory.

1) Diffusion layer model (Film Theory):

This is the simplest and most common theory for dissolution. The process of dissolution of solid particles in a liquid, in the absence of reactive or chemical forces, consists of two consecutive steps:

1. Solution of the solid to form a thin film or layer at the solid /liquid interface called as the stagnant film or diffusion layer which is soaked with the drug. This step is usually rapid³⁰.

2. Diffusion of the soluble solute from the stagnant layer to the bulk of the solution. This step is slower and is therefore the rate determining step in drug dissolution. The model is depicted in following in figure.

Fig 2: Diffusion layer model

The rate of dissolution when the process is diffusion-controlled and involves no chemical reaction was given by Noyes and Whitney:

Where, dc⁄dt =Dissolution rate of the drug.

k=Dissolution rate constant (First order).

Cs=Concentration of drug in the stagnant layer.

Cb=Concentration of drug in the bulk of the solution at time t.

· Flick’s first law of diffusion and modified the Noyes-Whitney′s equation.

Where, D=Diffusion coefficient of the drug.

A=Surface area of the dissolving solid.

Kw/o=water/oil partition coefficient of the drug considering the fact that dissolution body fluid are aqueous. since the rapidity with which drug dissolves depends on the kw/o. It is also called as the intrinsic dissolution rate constant.

V =Volume of dissolution medium.

h = Thickness of the stagnant layer.

(Cs-Cb) = Concentration gradient for diffusion of drug.

2) Danckwert’s Model:

· This theory supposes that solid solution equilibrium is achieved that at interface and mass transport is slow step in dissolution process.

· The agitated fluid consisting of macroscopic mass of eddies or packets reach the solid/liquid interface in a random fashion due to eddy currents, absorb the solute by diffusion and carry it to the bulk of the solution.

· Diffusions occur into each of the packets during short time in which the packet is in contact with surface of solid.

· Since the solvent packets are exposed to new solid surface each time, the theory is called as surface renewal theory³¹.

Fig 3: Danckwert′s model

The Danckwert’s model is expressed by equation:

Where, m = Mass of solid dissolved.

Rate of surface renewal (or the interfacial tension).

3) Interfacial Barrier Model (Double Barrier or Limited Solvation Theory):

· The diffusion layer model and the Danckwert’s model were based on two assumptions.

1) The rate determining step that controls dissolution is the mass transport.

2) Solid solution equilibrium is achieved at the solid/liquid interface.

· According to the interfacial barrier model an intermediate concentration can exist at the interface as the result of solvation mechanism and is a function of solubility rather than diffusion³².

· When considering the dissolution of a crystal and different interfacial barrier in the following equation;

Where,

G = Dissolution rate per unit area.

Ki= Effective interfacial transport constant.

Various Official Dissolution Test:

· Because dissolution tests provide the compendial relation to drug product performance.

· Dosages forms to be tested are –

· Immediate Release Dosage Forms: Powders, Granules, Beads, Capsules.

· Controlled Release Dosage Forms: Powders, Granules, Beads, Capsules.

· Transdermal System.

· Implants.

Official Dissolution Monograph:

According to I.P.and E.P. for solid dosage forms (tablets and capsules) dissolution apparatus used are:

1) Apparatus I-Paddle Apparatus

2) Apparatus II-Basket Apparatus

According to B.P. apparatus used are:

1) Apparatus I- Basket Apparatus

2) ApparatusII-Paddle Apparatus

3) Apparatus III- Flow Through Cell Apparatus

Table No. 1 - According to USP 30 dissolution apparatus used are:

Sr. No	USP Apparatus	Description	Rotation Speed	Dosage Form
1.	I	Basket	50-120 rpm	IR, DR, ER.
2.	II	Paddle	20-50 rpm	IR, DR, ER.
3.	III	Reciprocating Cylinder	6-35dpm	IR, ER.
4.	IV	Flow-Through Cell	N/A	ER Poorly Soluble API.
5.	V	Paddle Over Disk	25-50 rpm	Transdermal
6.	VI	Cylinder	N/A	Transdermal
7.	VII	Reciprocating Holder	30 rpm	ER.

Conditions (for all in general):

1) Temp.-37±0.5ºc.

2) PH-±0.05 unit in specified monograph.

3) Capacity-1000ml.

4) Distance between inside bottom of vessel and paddle /basket is maintained at 25±2mm.

5) For enteric coated dosage from it is first dissolved in 0.1 N HCl and then in buffer of pH 6.8 to measure drug release.

Apparatus: I –Basket Apparatus:

· The basket method was first described in 1968 by Pernarow-Ski, Woo and Searl.

· Unless otherwise specified in the individual monograph, use 40-mesh cloth.

· The apparatus consists of a motor a metallic drive shaft, a cylindrical basket and covered vessel made of glass or other inert transparent material.

· It is 160-175 mm high and has an inside diameter of 98-106 mm and a nominal capacity of 1000ml

· Basket is fabricated of stainless steel, type 316 or equivalent.

· Significant-Motion, agitation or vibration³³.

· Basket apparatus useful for-Capsules, Beads, Delayed Relesase/Enteric Coated dosages forms, Floating dosages forms.

· Advantages:

· Full pH change during the test.

· More than 200 monographs.

· Can be easily automated which is important for routine investigation.

· Disadvantages:

· Degassing is particularly important.

· Disintegration dissolution interaction.

· Limited volume sink condition for poorly soluble drugs

· Hydrodynamics Dead joint under the basket³⁴.

Apparatus II-Paddle Apparatus:

· The dosages form is allowed to sink to the bottom of the flask before rotation of the blade standard.

· The paddle apparatus for stirring rate exceeding 125 rpm.

· Used in the validated sinker devices.

· Paddle Apparatus useful for - Tablets, Capsules, Beads, Delayed Release, Enteric coated dosage forms.

· Advantages:

· PH change possible.

· Robust.

· Long experience

· Easy to used.

· Easily adapted to apparatus

· Disadvantages:

· Coning

Apparatus III-Reciprocating Cylinder:

· Reciprocating cylinder apparatus consists of a set of cylindrical, flat-bottomed glass vessels ;a set of glass reciprocating cylinders; inert fittings (stainless steel type 316 or other suitable material),and screens that are made up of suitable non-sorbing and non-reactive material and that are designed to fit into the tops and bottoms of the reciprocating.

· The tubes to be dipped sequentially in up to six different media vessels, using programs that vary the speed and duration of immersible³⁵.

· The reciprocating cylinder is allowed to move in upward and downward direction constantly.

· Reciprocating cylinder useful for-Tablets, Beads, Controlled release formulations.

· Advantages-

· Easily change the pH-profiles.

· Hydrodynamics can be directly affected by varying the dip rate.

· Disadvantages-

· Limited data.

· Small volume (max. 250 ml)

Apparatus IV –Flow through cell

· Limited volume apparatus with a finite volume of dissolution fluid suffer from the problem They operate under non-sink conditions³⁶.

· The drawbacks of non flow-through apparatus include-

I) lack of flexibility and homogenecity.

II) Establishment of conc. gradients.

· The flow-through apparatus has been developed, a dissolution cell of low volume (often ˂30ml) and a reservoir to provide fresh medium.

· The assembly consists of a reservoir, pump, heat exchanger, column (cell), tablet support and filter system

· The forces of pump the dissolution medium upwards through the flow-through cell.

· Placing glass beads in the bottom of cell.

· The floe rate of the dissolution medium through the cell must be specified for each product.

· Perform the analysis as directed in the individual monograph.

4: flow through cell

· Flow Through Cell useful for-Low solubility drugs, Micro-particulates, Implants, Controlled release formulations, Suppositories.

· Variations-

1) Open System.

2) Closed System.

· Advantages-

· Possibly pH profile.

· Easily change media pH.

· Sink conditions.

· Disadvantages-

· Volume of media high.

· Labor intensive.

· Deaeration necessary.

Apparatus V-Paddle over Disk:

· The used paddle apparatus (USP 2) with the sample, usually a transdermal delivery system attached to a stainless steel disk then placed at the bottom of the vessels.

· The paddle disk assembly holds the system flat and is positioned such that the release surface is parallel with the bottom of the paddle blade.

· The vessel may be closed during the test to reduce evaporation³⁷.

· Paddle over Disk useful for-Transdermal patches.

Apparatus VI-Cylinder:

· The vessels assembly from the basket apparatus with the basket being replaced by a stainless-steel cylinder.

· Apparatus is generally used for transdermal delivery systems by attaching to the outside of the cylinder²⁸.

· The dosage unit place on the cylinder at the beginning of each test, to the outermost of the cylinder such that the long axis of the system fits around the border of the cylinder and removes trapped air bubbles.

· Cylinders placed in the apparatus, and immediately rotate at the rate specified in the individual drug³⁸.

Apparatus VII-Reciprocating holder:

· The assembly consists of a sample holder that oscillates up and down in the medium vessel.

· The solution containers are partically immersed in a suitable water bath of any convenient size that allow to maintaining the temperature inside the containers at 32 ± 0.50^39.

· This apparatus may be used for transdermal products, coated drug delivery system, or osmotic pump devices.

· The sample is attached to the outside of the sample holder⁴⁰.

CONCLUSION:

The dissolution test apparatus studying various factors influencing the rate of dissolution. We can optimize the different properties of the formulation. By conducting dissolution studies won can know that batch to batch reproducibility. The best available tools which can at least quantitatively assure about the biological availability of drug from its formulation are its in vitro dissolution.

ACKNOWLEDGEMENT:

The authors are grateful to the authorities of Loknete Dr. J. D. Pawar College of Pharmacy, Manur for the facilities.

CONFLICT OF INTREST:

The authors declare no conflict of interest.

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Received on 18.03.2021 Modified on 15.05.2021

Asian J. Res. Pharm. Sci. 2021; 11(3):229-236.

DOI: 10.52711/2231-5659.2021.00037