A REVIEW Selection of Dissolution Media

7/27/2019 A REVIEW Selection of Dissolution Media

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A REVIEW: SELECTION OF DISSOLUTION MEDIA

DEFINATION: Dissolutionis the process by which a solid substance enters the solvent phase

to yield a solution i.e. mass transfer from solid surface to liquid phase. Dissolution Rate: It is the amount of drug substance that goes in solution per

unit time under standardized conditions of temperature and solvent

composition.

IMPORTANCE:

Dissolution testing is mainly used to confirm product quality and batch-to-batchconsistency.

Dissolution testing finds application in bioavailability problems andbioequivalence studies.

In R&D department, comparing In vitro dissolution data with In vivobioavailability,we would greatly facilitate product development.

Some of the steps involved in the absorption of drugs administered orally

from solid dosage forms. GI,gastrointestinal.

HISTORY OF DISSOLUTION:

It all started in 1897 with the first reference to dissolution: Noyes and Whitneypublish a paper on The Rate of Solution of Solid Substances in Their Own

Solution. They suggested that the dissolution rate was controlled by a layer ofsaturated solution that forms instantly around a solid particle.

A few years later in 1900, Brunner and Tolloczko proved that dissolution ratedepended on the chemical, physical structures of the solid, the surface area

exposed to the medium, agitation speed, medium temperature and the overall

design of the dissolution apparatus.


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1904-Nernst and Brunner modified the Noyes-Whitney equation by applyingFicks law of diffusion. A relationship between the dissolution rate and the

diffusion coefficient was established.

SELECTION OF DISSOLUTION MEDIA:

The selection of an appropriate dissolution medium is a fundamental stage of thedissolution test.

- It is more important that the test closely simulate the environment in the GI tract

than necessarily produce sink condition.

Sinkcondition:

The dissolution rate may be given by Novey-Whitney equation.

Where,S:surfaceareat:time

Cs Ct : concentration gradient between the concentration of solute in the

stagnantlayer

This is first order dissolution rate process, for which the driving force isconcentration gradient.

This is true for in-vitro dissolution which is characterized by non-sinkconditions.

The in-vivo dissolution is rapid as sink conditions are maintained by absorptionof drug in systemic circulation i.e. Cb=0 and rate of dissolution is maximum.

Under sink conditions, if the volume and surface area of the solid are keptconstant, then,

dW/dt = K

This represents that the dissolution rate is constant under sink conditions andfollows zero order kinetics.


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So, we have to maintain sink condition in in-vitro. This is can be achieved by,

i. Bathing the dissolving solid in fresh solvent from time to timeii. Increasing the volume of dissolution fluid

iii. Removing the dissolved drug by patitioning it from the aqueous phase of the

dissolution fluid into an organic phase placed either above or below the fluid, for

example, hexane or chloroform

iv. Adding a water miscible solvent such as alcohol to the dissolution medium

v. By adding selected adsorbent to remove the dissolved drug.

A sink condition occurs when the drug that can be dissolved in the dissolutionmedium is 3 times greater than the amount of drug to be dissolved.

Cs/Cd3 Suppose we have product with label claim 200mg and say solubility is 1 mg/ml

then oboviously 200 ml is sufficient for its solubility.If you maintan sink

conditions with say 220ml or 230 ml ithink it practically difficult to work with

or dissolutions with these small amounts of medium.Hence it is better to

maintain 3:1 ration.

- A flow-through system and reservoir may be used to provide sink conditions by

continually removing solvent and replacing it with fresh solvent .

- The dissolution characteristics of oral formulations should be evaluated over the

physiologic pH range of 1.2 -6.8.


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The pH of the stomach before and after meal.

From above we can say than the main difference seen in the Stomach pH,this isdue to the secreation of the gastric juice mainly HCl.

The Enteric coated tablet is tested using the basket or paddle apparatus initiallycontaining 750 ml of 0.1N HCl. After two hours of exposure, a sample is

removed for analysis, 250 ml of phosphate buffer is immediately added and the

mixed contents of the dissolution vessel adjusted to a pH of 6.80.05. For very poorly soluble compounds, aqueous solutions may contain a

percentage of a surfactant (e.g., sodium lauryl sulfate, Tween 80, Cremophor,

Triton, terigitol, cyclodextrin or Span 80) that is used to enhance drug

solubility.

The need for surfactants and the concentrations used should be justified dued toits toxicity.

The surfactant is added to mimic the action of the Bile saltsKEY OPERATING PARAMETERS:

VOLUME: The recommended volume of dissolution medium is 900mL when using the

basket or paddle apparatus.

The volume can be raised to between 2 and 4 L, depending on the concentrationand sink conditions of the drug solution.

* TEMPERATURE:


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The standard temperature for the dissolution medium is 370.5C for oraldosage forms.

Slightly increased temperatures such as 380.5C have been recommended fordosagesforms such as suppositories.

Lower temperatures such as 320.5C are utilized for topical dosage formssuch as transdermalpatches and topical ointments.

* DEAERATION:

Air bubbles can interfere with the test results. Bubbles on the dosage unit may decrease the dissolution rate by decreasing the

available surface area.

Some formulations will be sensitive to the presence of dissolved air in thedissolution.

Media containing surfactants are not usually deaerated after the surfactant hasbeen added to the medium.

The USP deaeration method requires heating of the medium, followed byfiltration,and drawing of a vacuum for a short period of time. Other deaeration

methods such as room temperature filtration, sonication,and helium sparging

are described in literature.

The deaeration method needs to be clearly characterized, since the methodchosen might impact the dissolution release rate. It should be noted that

dissolution tests using the flowthroughcell method could be particularly

sensitive to thedeaeration of the medium.

Media containing surfactants are not usually deaerated after the surfactant hasbeen addedto the medium because of excessive foaming.

- Once the appropriate dissolution conditions have been established,the method

should be validated for linearity, accuracy,precision, specificity, and

robustness/ruggedness.

- All dissolution testing must be performed on a calibrated dissolution apparatus

meeting themechanical and system suitability standards specified in the appropriate

compendia.

- Therefore, the development and validation of a scientifically sound dissolution

method requires the selection of key method parameters that provide accurate,

reproducible datathat are appropriate for the intended application of the

methodology.


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COMPENDIAL DISSOLUTION MEDIA:

These media are given in the USP.

* Simulated Gastric Fluid:

The traditional medium to simulate gastric conditions in the fasted state hasbeen simulated gastric fluid (SGF) of theUSP.

This medium contains hydrochloric acid and sodiumchloride, as well as pepsinand water, and has a pH of 1.2.

Although the medium addresses many of the qualities ofgastric juice, there aresome aspects that could be optimized.

For example, most studies of gastric pH indicate that the across-the-boardaverage gastric pH usually lies in the range1.51.9 .

For weak acids and neutral compounds, this small difference makes absolutelyno difference in the dissolution characteristics, but for very poorly soluble

weakbases, the dissolution results in compendial SGF are likely to overestimate

the in vivo dissolution rate.

Further deviations from gastric physiology are the pepsin concentration, whichis very high compared to that observed in gastric juice aspirated under fasted

state conditions and the surface tension of about 70 mN/m that does not take

into account the much lower average surface tension of human gastric fluid,

which has been repeatedly measured as lying in the 35- to 50-mN/m range .

* Water:

Water is an attractive medium that because of itssimplicity has been widelyused for quality control purposes.

It could even be argued that it is physiologically relevant since manyformulations are intended to be ingested with a glass ofwater.

Furthermore, in those patients with hypochlorhydria (elevated gastric pH), dueto aging and/or co-therapy with H2 receptor antagonists and proton pump

inhibitors, water maybe a somewhat suitable medium as it roughly reflects

theincreased gastric pH and the low buffer capacity.

However, the pH of water may vary with its source, and water has no buffercapacity. Thus, for the latter purpose, a better alternative, which would be more

biorelevant in this context, is a diluted HCl/NaCl solution or a diluted acetate

buffer witha final pH of around 5.

* Simulaed Intestinal Fluid:


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A frequently used medium for the simulation of small intestinal (SI) conditionsin the fasted state is simulatedintestinal fluid (SIF), a medium that was first

described as standard test solution in the USP more than 50 years ago.

The only parameter that has been changed is the pH of themedium. As it was assumed that the pH in the small intestine is very close to blood

plasma, the pH of SIF was initially set at 7.5.

However, subsequent examinations of the pH in the intestinal tract revealedthat a pH gradient exists within the small intestine, that the pH becomes less

acidic at more distal locations, and that pH values close to 7.5 can only be

measured in the terminal ileum.

As per above the 7.5 is mainly seen at the distal part so the we cant predict the

whole intestine.

The use of an in vitro medium with an unsuitably high pH in contrast would most

probably lead to false positive results, especially for poorly soluble, weakly acidic

drugs and entericcoated dosage forms. Thus, with USP 24/NF19 , the pH of the

compendial SIF was revised to pH 6.8, which cantypically be measured in the mid-

jejunum.

* BIORELEVENT MEDIA:

Biorelevant is short for biologically relevant.


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Biorelevant media are virtually the same as intestinal juices. They contain keynatural surfactants (bile salts, phospholipids) present in intestinal juices. These

are missing from ordinary dissolution media.

They are virtually the same as the fluids inside the body, it can provide a muchmore accurate picture of how drugs and their formulations are likely to dissolvein vivo.

The aims are to highlight potential bioavailibility issues and attempt to achieveIVIVC.

Biorelevant media include Fasting state and Fed state simulated GastroIntestinal fluids.

* Fasted State Gastric Conditions: FaSSGF:

Several attempts have been made to improve simulation of fasting conditions inthe stomach. In most of these media, particular attention was given to the

simulation of the surfacetension measured in human gastric aspirates. However, in these media, non-physiologically relevant surface active agents,

lower than physiological pH values or by far too highconcentrations of pepsin

or bile salts, were utilized.

Recently, a fasted state simulated gastric fluid (FaSSGF) containing pepsin andlow amounts of bile salt and lecithin was developed byVertzoni .

Vertzoni compared the solubility of four poorly soluble drugs in human gastricapirates and different kinds of simulated gastric fluids.

In these experiments, they could clearly show that compared with data in otherfrequently usedmedia, solubility data in FaSSGF provide a better basis forthe

assessment of intragastric solubility during a BA study inthe fasted state.

Thus, to better predict drug solubility and dissolution rate in the fasted stomach,the use of FaSSGF isstrongly recommended for future in vitro experiments.

Sodium taurocholate was chosen as a representative bile salt because cholicacid is one of the more prevalent bile salts in human bile.

For this media Standard paddle or basket apparatus used.


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The Composition for Simulating Fasted State Gastric Conditions (FaSSGF)

* Fasted State Small Intestinal Conditions: FaSSIF:

Specifically fasted state simulating intestinal fluid (FaSSIF) was developed tosimulate fasting conditions inthe proximal small intestine.

The addition of a stable phosphate buffer system that results in a pHrepresentative to valuesmeasured from the mid-duodenum to the proximal

ileum.

This medium contains bile salts and phospholipids (lecithin). These compounds facilitate the wetting of solids and thesolubilization of

lipophilic drugs into mixed micelles.

Thus, the dissolution of poorly soluble, lipophilic drugs may beenhanced. Sodium taurocholate was chosen as a representative bile salt because cholic

acid is one of the moreprevalent bile salts in human bile.

From pharmacokinetic studies of drug absorption in the fasted state,ingesting200250 ml of water with the dosage form, a maximum total volume of about

300500 ml will be available in the proximal SI. Therefore, for dissolution

tests, a volume of 500 ml is recommended.


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Composition of the Simulate Fasted State Conditions in the Small Intestine

(FaSSIF)

* Fed State Gastric Conditions: Milk and Ensure Plus:

Is the fed state, the luminal composition in the stomach will be highlydependent on the composition of the meal ingested.

The composition and the amount of the food is different in the every people,sowe cant get correlation.

However, none of these media reflects all parameters that are important fordetermining food effects on drugrelease in the stomach.

The ideal medium representing initial gastric conditions in the fed state shouldhave similar nutritional and physicochemical properties to that of a meal, e.g.,the standard breakfast recommended by the US FDAto studying the effects of

food in BA and bioequivalence studies.

Milk was first investigated as a dissolution medium about 20 years ago, the useof Ensure Plus has been established only a few years ago.

Ensure Plus have a similar composition to a breakfast meal with respect to theratio ofcarbohydrate/fat/protein.

The pH (6.56.6) and additional physicochemical properties are similar to thoseof homogenized and undigested standard breakfasts, whereas Ensure Plus

comes closer to the properties of the FDA breakfast. In addition, as thestability of fresh milk at 37C is a problem, heat-treated

milkmust be used.


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The Composition of Fed State Simulated Gastric Fluid(FeSSGF)

* Fed State Small Intestinal Conditions: FeSSIF:

As in the stomach, conditions for drug dissolution in the proximal part of thesmall intestine are highly dependent onwhether the drug is dosed in the fed or

the fasted state.

Afteringesting a meal, there are changes in both the hydrodynamicsand theintralumenal volume.

The pH of the chime after a solid meal is lower than the intestinal fluid pH inthefasted state, while buffer capacity and osmolality show asharp increase.

As well as these factors, the sharp increase in bile output could also be a majorinfluence onthe BA of a drug.

Composition of Medium Used to Simulate Fed State Conditions in the Small

Intestines (FeSSIF)


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- In order to achieve the higher buffer capacity and osmolality, while maintaining

the lower pH value, representativeof fed state conditions in the proximal small

intestine, FeSSIF contains an acetate buffer.

- Taurocholate and lecithinare present in considerably higher concentrations than

in thefasted state medium to reflect the biliary response to mealintake.

Here is one example of Danadrol. The dissolution rate is maximum with the FeSSIF, than FaSSIF, than the SIF.

APPRATUS RECOMMENDED BASED ON DOSAGE FORM TYPE:

Type of dosage form RecommendedApparatus

Solid oral dosage formsBasket, paddle, reciprocating,

cylinder, or flow-through cell

(conventional)

Oral suspensions Paddle

Oral disintegrating tablets Paddle

Chewable tabletsBasket, paddle, or reciprocating,

cylinder with glass beads

Transdermalsspatches Paddle over disk

Topicals semisolids Franz cell diffusion system


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SuppositoriesPaddle, modified basket, or dual,

chamber flow-through cell

Chewing gum

Special apparatus [European

Pharmacopoeia (PhEur)]

Powders and granulesFlow-through cell

(powder/granule sample cell)

Microparticulate

formulationsModified flow-through cell

Implants Modified flow-through cell

ROTATION SPEED OF APPARATUS:USP

APPARATUSDESCRIPTION

ROTATION

SPEEDDOSAGE FROM

I Basket 50-120 rpm IR,DR,ER

II Paddle 12-50 rpm IR,DR,ER

IIIReciprocating

cylinder

6-35 rpm IR.ER

IV Flow through cell N/AER,POORLY

SOLUBLE API

V Paddle over disk 25-50 rpm TRANSDERMAL

VI Cylinder N/A TRANSDERMAL

VIIReciprocating

holder

30 rpm ER

Where, IR=Immediate Release;DR=Delayed Release;ER=Extened Release

RECOMMENED DISSOLUTION MEDIUM COMPOSITION & VOLUME

FOR ROTATING BASKET OR ROTATING PADDLE APPARATUS:

Guidance or Volume pH Additives


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compendial

reference

Federation

International

Pharmaceutique

(FIP) (23)

5001,000

mL;900mLhistorical;

1,000mL

recommended

for future

development

pH 16.8;

above pH6.8 with

justification

not

to exceed pH

8

Enzymes,salts,

surfactants

with

justification

United States

Pharmacopeia

(USP) (10

12)

5001,000

mL; up

to 2,000mL

for

drug withlimited

solubility

Buffered

aqueous

solution pH

48 or

dilute acid

solutions(0.001N

HCl to 0.1N

HCl)

Enzymes,

salts,surfactants

balanced

against

loss of

discriminatory

power;

enzymes can

beused for

crosslinking

of gelatin

capsules or

gelatin-coated

tablet

Guidance or

compendialreferenceVolume pH Additives

World Health

Organization

Determined

per

Adjust pH

to within

Determined

per


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(WHO) (16),

European

Pharmacopoeia

(PhEur) (14),Japanese

Pharmacopoeia

(JP) (15)

product 0.05

units of

the

prescribedvalued

product

FDA (8,9)

500, 900,

or1,000mL

pH 1.2

6.8;

higher

pH

justified

caseby-casein

general

not to

exceed

pH 8

Surfactants

recommended

for

water poorly

soluble drug

products

need

and amount

should be

justified;

enzymes

use needcase-bycase

justification;

utilized for

the

cross-linking

of

gelatin

capsulesor gelatin-

coated

tablets

FACTOR AFFECTING DISSOLUTION RATE:


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Some of the more important factors that affect the dissolution rate, especially,of slowly dissolving or poorly soluble substances.

The various physicochemical properties of drug that affect drug dissolution are,

Surface area and particle size The crystal form of a drug

The state of hydration

Complexation

Chemical modification

Drug pKa& GI pH

Of the above factor,the aim of all is to increase the drug solubility. As drug is soluble ,it more absorption and increase the Bioavialability.* Surface area and particle size : For better dissolution, the reduction of the particle size of the drug has been the

most thoroughly investigated.

There are two type of surface area of the particle, Absolute surface area which is the total surface area of any particle. Effective surface area which is the area of solid surface exposed to the

dissolution medium.

A drug dissolves more rapidly when its surface area is increased. This increasein surface area is accomplished by reducing the particle size of the drug.

This is the reason why many poorlysoluble and slowly dissolving drugs aremarketed in micronized or microcrystalline form.

The reduction in particle size and, therefore, surface area is accomplished byvarious means(e.g. milling, grinding and solid dispersions).

Below are the examples of drugs where bioavailability hasbeen increased as aresult of particle size reduction.

Aspirin. Bishydroxycoumarin, Chloramphenicol, Digoxin,

Fluocinoloneacetonide, Griseofulvin, Medroxyprogesterone

acetateNitrofurantoin, Phenobarbital, Phenacetin, Procainepenicillin,

Reserpine

Spironolactone, Sulfadiazine, Sulfisoxazole, Sulfur,

Tolbutamide, Vitamin A


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Lets consider the example of the Sulfadiazine. From the graph we can say that the Microcrystalline form will dissolve more

than the regulare form.

The smaller the particle size the larger the specificsurface and the faster thedissolution.

* Crystalline versus amorphous form:

Some drugs exist as either crystalline or amorphous form,there is the possibilitythat there will be significant differences in their bioavailability.

Many drugs exist in more than one crystalline form, a property known aspolymorphism,and each form called polymorpgh.

Though chemically the same, polymorphs differ substantially with regards tophysicochemical properties.These properties include solubility, dissolution rate,

density and melting point, among others.

At any one temperature and pressure, only one crystal (polymorph) form will bestable.

Any other polymorph found under these condition is metastable and willeventually convert to the stable form.

The dissolution of different solid form of drug is amorphous > metastable >stable.

A chloramphenicol palmitate have 3 polymorph; A,B and C.Among three Bform have best bioavailability.


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Name of drug Number of polymorphs

Chloramphenicol palmitate

Chlordiazepoxide HCI

Cortisone acetate

Erythromycin

Indometacin

Prednisone

Progesterone

Testosterone

3

2

8

2

3

1

2

4

* State of hydration:

The state of hydration of a drug molecule can affect some of thephysicochemical properties ofa drug.

One such property that is significantly influenced by the state of hydration isthe aqueous solubility of the drug.

The anhydrous form of a compound is more soluble than the hydrate. This is because the hydrate from already have a water molecule so it cant be

more react with water.

This difference in solubility is reflected in differences in the dissolution rate. A study was performed on ampicillin, a penicillin derivative that is available

as the anhydrous form and the trihydrate form. The anhydrous form will welldissolved.

The first graph will show the solubility of the ampicillin,we observed that theAnhydrous form have more solubility than trihydrate form.

As the Anhydrous form will greater solibility the dissolution will be more,itshown in the second graph.


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Solubility of the ampicillin

Dissolution of the ampicillin

* Complexation : Formation of a complex of drugs in the GI fluid may alter the rate and, in some

cases, the extent of absorption.

The complexing agent may be a substance normal to the GI tract, a dietarycomponent or a component (excipient) of a dosage form.

Intestinal mucus, which contains the polysaccharide mucin, can bindstreptomycin and dihydrostreptomycin,this binding may contribute to the poor

absorption of these antibiotics.


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Tetracycline forms insoluble complexes with calcium ions. Absorption of theseantibiotics is substantially reduced if they are taken with milk.

The most frequently observed complex formation is between various drugs andmacromolecules such as gums, cellulose derivatives, high- molecular-weight

polyol and non-ionic surfactants. The dissolution and absorption rates of phenobarbital containing th

Polyethylene glycol 4000 (PEG4000)ispolyol are reported to be markedly

reduced.

* Drug pKa and GI pH : In acidic medium, lots of protons are present. Therefore, greater amount of

acidic drug is unionized and increases its absorption. So the acidic drugs are

better absorbed from the stomach.

Basic drugs get ionized in acidic medium, thus this form is poorly absorbed. A weak acid such as aspirin (pKa 3.5) is approximately 99% unionized in the

gastric fluid at pH 1.0 but only 0.1% of aspirin is unionized at pH 6.5(small

intestine).

The amount of exists of unionised is function of dissociation constant. For a acidic drug pKa value should be more. And pKa value for basic should be

less.

Drug pKa pH/site of absorption

Very weak acid (pKa> 8.0

Pentobarbital

Hexobarbital

Phenytoin

Ethosuximide

8.1

8.2

8.3

9.3

Unionized at all pH

values;

Absorbed along the entire

length of the GIT

Moderately weak acids (pKa 2.5 to 7.5)

Cloxacillin

AsprinIbuprofen

Phenylbutazone

2.7

3.54.4

4.5

Unionized in gastric pH

and ionized in intestinalpH;better absorbed from

stomach

Strong acids (pKa< 2.5)


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Disodium cromoglycate 2.0Ionized at all pH;poorly

absorbed from

Very weak base (pKa< 5.0)

Theophylline

Caffeine

Oxazepam

Diazepam

0.7

0.8

1.7

3.7

Unionized at all pH

values;

Absorbed along the entire

length of the GIT

Moderately weak bases (pKa 5 to 11)

Reserpine

HeroinCodeine

Amitriptyline

6.6

7.88.2

9.4

Ionized at gastric pH,

Unionized at intestinalpH;better absorbed from

stomach

Strong acids (pKa> 11)

Mecamylamine

Guanethedine

11.2

11.7

Ionized at all pH;poorly

absorbed from

REFERENCES:

Encylopedia of Pharmaceutical Technology,third edition by James swarbrick. Pharmaceutical Dissolution Testing by Jennifer Dressman and Johannes

Krmer.

Basic Pharmacokinetics by Sunil S Jambhekar and Philip J Breen. Biopharmacetics and phamrcokinetic b D.M.Brahmankar. USP 2007 The AAPS Journal, Vol. 12, No. 3, September 2010. Indian J.Pharma Sci.2011 73 (3).

A REVIEW Selection of Dissolution Media

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