Selection of Dissolution Media – A Review

DEFINATION:

• “Dissolution is 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-batch consistency.
• Dissolution testing finds application in bioavailability problems and bioequivalence studies.
• In R&D department, comparing In vitro dissolution data with In vivo bioavailability,we would greatly facilitate product development.

Reference Id: PHARMATUTOR-ART-1971

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 Whitney publish 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 of saturated solution that forms instantly around a solid particle.
• A few years later in 1900, Brunner and Tolloczko proved that dissolution rate depended 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.
• 1904-Nernst and Brunner modified the Noyes-Whitney equation by applying Fick’s 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 the dissolution test.

– It is more important that the test closely simulate the environment in the GI tract than necessarily produce sink condition.

– SINK CONDITION:
The dissolution rate may be given by Novey-Whitney equation.

Where, S : surface area
t: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 is concentration gradient.
• This is true for in-vitro dissolution which is characterized by non-sink conditions.
• The in-vivo dissolution is rapid as sink conditions are maintained by absorption of 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 kept constant, then,

dW/dt = K

• This represents that the dissolution rate is constant under sink conditions and follows zero order kinetics.

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 time
ii. 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 dissolution medium is 3 times greater than the amount of drug to be dissolved.
• Cs/Cd≤3
• 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.

The pH of the stomach before and after meal.

• From above  we can say than the main difference seen in the Stomach pH,this is due to the secreation of the gastric juice mainly HCl.
• The Enteric coated tablet is tested using the basket or paddle apparatus initially containing 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 6.8±0.05.
• 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 to it’s toxicity.
• The surfactant is added to mimic the action of the Bile salts

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 concentration and sink conditions of the drug solution.

* TEMPERATURE:

• The standard temperature for the dissolution medium is 37±0.5°C for oral dosage forms.
• Slightly increased temperatures such as 38±0.5°C have been recommended for dosagesforms such as suppositories.
• Lower temperatures such as 32±0.5°C are utilized for topical dosage forms such 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 the dissolution.
• Media containing surfactants are not usually deaerated after the surfactant has been added to the medium.
• The USP deaeration method requires heating of the medium, followed by filtration,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 method chosen 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 has been 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.

COMPENDIAL DISSOLUTION MEDIA:
These media are given in the USP.

* Simulated Gastric Fluid:

• The traditional medium to simulate gastric conditions in the fasted state has been simulated gastric fluid (SGF) of theUSP.
• This medium contains hydrochloric acid and sodiumchloride, as well as pepsin and water, and has a pH of 1.2.
• Although the medium addresses many of the qualities ofgastric juice, there are some aspects that could be optimized.
• For example, most studies of gastric pH indicate that the across-the-board average gastric pH usually lies in the range1.5–1.9 .
• For weak acids and neutral compounds, this small difference makes absolutely no 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, which is  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 widely used for quality control purposes.
• It could even be argued that it is physiologically relevant since many formulations are intended to be ingested with a glass ofwater.
• Furthermore, in those patients with hypochlorhydria (elevated gastric pH), due to 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 buffer capacity. 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:

• A frequently used medium for the simulation of small intestinal (SI) conditions in 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  revealed that 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 can’t 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’.
• Biorelevant media are virtually the same as intestinal juices. They contain key natural 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 much more accurate picture of how drugs and their formulations are likely to dissolve in vivo.
• The aims are to highlight potential bioavailibility issues and attempt to achieve IVIVC.
• Biorelevant media include Fasting state and Fed state simulated Gastro Intestinal fluids.

* Fasted State Gastric Conditions: FaSSGF:

• Several attempts have been made to improve simulation of fasting conditions in the 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 and low amounts of bile salt and lecithin was developed byVertzoni .
• Vertzoni compared the solubility of four poorly soluble drugs in human gastric apirates and different kinds of simulated gastric fluids.
• In these experiments, they could clearly show that compared with data in other frequently 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 cholic acid is one of the more prevalent bile salts in human bile.
• For this media Standard paddle or basket apparatus used.

The Composition for Simulating Fasted State Gastric Conditions (FaSSGF)

* Fasted State Small Intestinal Conditions: FaSSIF:

• Specifically fasted state simulating intestinal fluid (FaSSIF) was developed to simulate fasting conditions inthe proximal small intestine.
• The addition of a stable phosphate buffer system that results in a pH representative 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,ingesting 200–250 ml of water with the dosage form, a maximum total volume of about 300–500 ml will be available in the proximal SI. Therefore, for dissolution tests, a volume of  ≤500 ml is recommended.

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 highly dependent on the composition of the meal ingested.
• The composition and the amount of the food is different in the every people,so we can’t get correlation.
• However, none of these media reflects all parameters that are important for determining food effects on drugrelease in the stomach.
• The ideal medium representing initial gastric conditions in the fed state should have 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 use of Ensure® Plus has been established only a few years ago.
• Ensure® Plus have a similar composition to a breakfast meal with respect to the ratio ofcarbohydrate/fat/protein.
• The pH (6.5–6.6) and additional physicochemical properties are similar to those of 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 37°C is a problem, heat-treated milkmust be used.

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 the small 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 the intralumenal volume.
• The pH of the chime after a solid meal is lower than the intestinal fluid pH in thefasted state, while buffer capacity and osmolality show asharp increase.
• As well as these factors, the sharp increase in bile output could also be a major influence onthe BA of a drug.

Composition of Medium Used to Simulate Fed State Conditions in the Small Intestines (FeSSIF)

– 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:

ROTATION SPEED OF APPARATUS:

RECOMMENED DISSOLUTION MEDIUM COMPOSITION & VOLUME FOR ROTATING BASKET OR ROTATING PADDLE APPARATUS:

FACTOR AFFECTING DISSOLUTION RATE:

• 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 increase in surface area is accomplished by reducing the particle size of the drug.
• This is the reason why many poorlysoluble and slowly dissolving drugs are marketed in micronized or microcrystalline form.
• The reduction in particle size and, therefore, surface area is accomplished by various means(e.g. milling, grinding and solid dispersions).
• Below are the examples of drugs where bioavailability hasbeen increased as a result of particle size reduction.

• Let’s 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 the dissolution.

* Crystalline versus amorphous form:

• Some drugs exist as either crystalline or amorphous form,there is the possibility that there will be significant differences in their bioavailability.
• Many drugs exist in more than one crystalline form, a property known as polymorphism,and each form called polymorpgh.
• Though chemically the same, polymorphs differ substantially with regards to physicochemical 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 be stable.
• Any other polymorph found under these condition is metastable and will eventually 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 B form have best bioavailability.

* State of hydration:

• The state of hydration of a drug molecule can affect some of the physicochemical properties ofa drug.
• One such property that is significantly influenced by the state of hydration is the 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 can’t 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 well dissolved.
• The first graph will show the solubility of the ampicillin,we observed that the Anhydrous form have more solubility than trihydrate form.
• As the Anhydrous form will greater solibility the dissolution will be more,it shown in the second graph.

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 dietary component or a component (excipient) of a dosage form.
• Intestinal mucus, which contains the polysaccharide mucin, can bind streptomycin and dihydrostreptomycin,this binding may contribute to the poor absorption of these antibiotics.
• Tetracycline forms insoluble complexes with calcium ions. Absorption of these antibiotics is substantially reduced if they are taken with milk.
• The most frequently observed complex formation is between various drugs and macromolecules 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.

REFERENCES:

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

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