a review on composition and preparation of ......2017/10/15 · 2 lecithin 0.02 mm 0.02 3 sodium...

www.wjpps.com Vol 6, Issue 12, 2017.

437

Swapna et al. World Journal of Pharmacy and Pharmaceutical Sciences

A REVIEW ON COMPOSITION AND PREPARATION OF

BIORELEVANT MEDIA

Gumpula Swapna*1, Ch. Malathi Suvarna

2, Merugu Manasa

3, N. Siva Subramanian

4,

G. Sandesh5 and J. Suprabath

6

1Department of Pharmaceutical Analysis, Gland Institute of Pharmaceutical Sciences,

Kothapet, Narsapur, Medak District, Telangana.

2Department of Pharmacology, Gland Institute of Pharmaceutical Sciences, Kothapet,

Narsapur, Medak District, Telangana.

3Department of pharmaceutical Analysis, Pulla Reddy Institute of Pharmacy, Dundigal.

4Principal, Head of the Department, Department of Pharmaceutical Chemistry, Gland

Institute of Pharmaceutical Sciences, Kothapet, Narsapur, Medak District, Telangana.

5Department of Regulatory Affairs, SCIENT Institute of Pharmacy, Ibrahimpatnam, Ranga

Reddy District, Telangana.

6Department of Pharmaceutics, Gland Institute of Pharmaceutical Sciences, Kothapet, Narsapur,

Medak District, Telangana.

ABSTRACT

Biorelevant Media are biologically relevant fluids which are incredibly

accurate simulations of juices found in the gut at various times of day.

Biorelevant media is used to reproduce the conditions in the

gastrointestinal (GI) tract In-vitro, so that the behavior of drugs and

dosage forms in the GI tract can be studied in the laboratory.These are

used for In-vitro solubility and dissolution studies along with the study

of decomposition under GI conditions along with the determination of

permeability of the drug. During the development of new a product,

testing it in Biorelevant Media can be of more help to predict its

behaviour during its entry and movement along the gut than with the

traditional buffers. Biorelevant Media can help to establish the product

solubility, time of solubility in gut, location of drug release in gut, effect of different

substances on absorption of drug by In-vitro experiments since, the failure of a drug or active

agent from its formulation or its dissolution in the gut fluids at the right time, will lead to

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 6.647

Volume 6, Issue 12, 437-449 Review Article ISSN 2278 – 4357

Article Received on

15 Oct. 2017,

Revised on 06 Nov. 2017, Accepted on 27 Nov. 2017,

DOI: 10.20959/wjpps201712-10663

*Corresponding Author

Gumpula Swapna

Department of

Pharmaceutical Analysis,

Gland Institute of

Pharmaceutical Sciences,

Kothapet, Narsapur, Medak

District, Telangana.


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decreased or no absorption by the body.This review article particularly discloses novel

compositions and method for preparing reproducible and consistent fasted state and fed state

bio relevant media such as FaSSIF, FaSSGF, FaSSIF-V2, FaSSIF-midgut, Dog FaSSIF, Dog

FaSSGF, FaSSCoF, FeSSIF, FeSSIF-V2, FeSSIF-midgut, FeSSCoF defined by selected

Biorelevant components and physicochemical parameters that simulate fasted state fluids in

the stomach and intestine.

KEYWORDS: Biorelevant media, Gut, FaSSIF, FeSSIF, FaSSGF, FeSSGF, FeSSCoF,

FaSSCoF.

INTRODUCTION

In-vitro evaluation of drugs for solubility and dissolution has been done through the ages

using the same buffer solutions which led to unsatisfactory results. Buffer solutions do not

resemble the ideal conditions of Gastro Intestinal Tract (GIT) which lead to miscalculation of

drug characteristics. For a formulation to be optimized its bioavailability should be studied

In-vitro and In-vivo. Since the In-vitro conditions are not ideal an alternative and most

effective method is being used which is known as In-vitro In-vivo correlation (IVIVC)

method to validate the physiological characteristics of drug. Given below in Fig. 1 is the

example of comparison of In-vitro and In-vivo studies of dissolution profile of Datranol. In

this method instead of using glass or Perspex beakers and buffers an artificial environment is

being simulated with the help of Biorelevant Media (BRM). BRM are incredibly accurate

simulations of gastric juices found in our gut at various times and conditions such as fasted

state and fed state. In BRM Taurocholic Acid and lecithin are used as surfactants to solubilise

the drugs in dissolution media as it occurs In-vivo.[1]

Fig. 1: Comparison of In-vitro and In-vivo studies of dissolution profiles of Datranol.


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BRM even though used for the In-vitro studies it also plays a prominent role in the

determination of decomposition of drug in the GI conditions as well as their permeability. It

is being recommended that all drugs are to be tested at all conditions of GIT. Media with

compositions similar to small intestine as well as stomach are to be used. Media for this

purpose are also available in the form of ready to mix powders. These ready to mix media can

be of very useful for bulk studies and analytical studies. The objective of this review is to

provide compositions for such media to facilitate preparation of fresh media.

1. The studies are usually conducted in BRM which may be fed state or fasted state. Fasted

state media is composed of bile salt, phospholipid and fed state media contains fatty acids and

monoglycerides representing lipolysis products. Much care is taken during composition so as

to maintain the analytical similarities which may pose a problem while comparing the

physicochemical properties. The components to be used for making an ideal BRM have not

yet been selected or optimized with respect to a key performance parameter, the surface

tension. The need for media which can be used for precise and accurate results is still unmet.

Use of BRM improves the chances of production of better quality formulation by CRO‟s and

innovators with reduced use of animals.[2]

BRM facilitates the easy correlation between In-vitro and In-vivo studies of drug dissolution

studies which in turn helps in the reduction of cost and time of these studies.

There are different BRMs with varying compositions depending on the state of GIT or

condition the researcher is willing to simulate. All compositions commonly comprise of

surfactants, enzymes and other components that are available in the physiological

environment. Here are a few compositions that could be used to prepare BRMs with ease.

Conversion of millimoles to grams[3]

1 Millimole = 0.001 moles

Grams = moles * molecular weight


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1. Composition of different bio relevant media[4]

List Ingredients and Their Molecular Weights Used in Biorelevant Medium

Table no.1.

S. No Name of The Ingredient Molecular

Weight(Grms/Mole) Uses

1 Sodium hydroxide 39.997 gr/mole Adjust pH

2 Maleic acid 116.072 Buffer

3 Tris 121.14 buffer

4 Glucose 180.1559 Energy replenisher

5 Sodium oleate 304.45 Bile salt

6 Lecithin 758.06 Natural surfactant

7 Sodiumcholate 430.561 Bile salt

8 Sodium chloride 2.16 Adjusts osmolarity

9 Lysolecithin 523.692 Co-surfactant

10 Sodiumtaurodeoxycholate 539.704 Bile salt

11 Sodiumtaurocholate 537.688 Natural bile salt

12 Monobasic sodium phosphate 119.98 Buffer

13 Glyceryl monooleate 356.55 Lipid (permeation enhancer)

14 Hydrochloric acid 36.46094 Adjust pH

15 Acetic acid 60.05 Buffer

FaSSIF: Fasted State Simulated Intestinal Fluid

Table no. 2.

S. No Ingredients Weight in millimoles Weight in grams

1 Sodium taurocholate 3.0 mM 1.61

2 Lecithin 0.75 mM 0.57

3 Monobasic sodium phosphate 28.4 mM 3.40

4 Sodium hydroxide 8.7 mM 0.35

5 Sodium chloride 105.9 mM 0.23

FaSSIF Media has a pH of 6.5 and an osmolality of about 270+/-10 mOsmol/kg. buffer pH

(mM/dpH).

FeSSIF': Fed State Simulated Intestinal Fluid

Table no. 3.


1 Sodium taurocholate 15 mM 8.06


3 Acetic acid 144.1 mM 8.66



FeSSIF Media has a pH of 5.0 and an osmolality of about 670+/-10 mOsmol/kg. buffer pH

(mM/dpH).


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FaSSGF': Fasted State Simulated gastric Fluid

Table no. 4.

S.No Ingredient Weight in millimoles Weight in grams




4 Hydrochloric acid +/-25.1 mM 0.92

FaSSGFMedia has a pH of 1.6 and an osmolality of about 120+/-2.5 mOsmol/kg. which is

not buffered medium.

SIF Ileum Simulated Intestinal Fluid

Table no. 5.




3 Maleic acid 52.8 mM 6.13

4 Sodium hydroxide 105 mM 4.2


SiF ileum Media has a pH of 7.5 and an osmolality of about 190 mOsmol/kg. and buffer

capacity (mM/dpH).

FaSSIF V2: Fasted State Simulated Intestinal Fluid.

Table no. 6.







Fasted state‟ simply means without food or before a meal. This state is also sometimes

referred to as „pre-prandial‟.

Media has a pH of 6.5 and an osmolality of about 180+/-10 mOsmol/kg. and buffer capacity

(mM/dpH).


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FaSSIF midgut: Fasted State Simulated Intestinal Fluid.

Table no. 7.

S.No Ingredients Weight in milli moles Weigt in grams

1 Sodium taurocholate 1.5mM 0.81





Media has a pH of 6.8 and an osmolality of about 190 mOsmol/kg. and buffer capacity

(mM/dpH).

FeSSIF-V2: Fed State Simulated Intestinal Fluid.

Table no. 8.

S.No Ingredients Weight in millimoles Weight in grams

1 Sodium taurocholate 10mM 5.38

2 Lecithin 2 mM 1.52

3 Sodium oleate 0.8 mM 0.24

4 Glycerol monooleate 5 mM 1.78




Media has a pH of 5.8 and an osmolality of about 390+/-10 mOsmol/kg. and buffer capacity

(mM/dpH).

FeSSIF midgut: Fed State Simulated Intestinal Fluid.

Table no. 9.


1 Sodium taurocholate 5mM 2.69

2 Lecithin 1 mM 0.76

3 Sodium oleate 0.4mM 0.12

4 Glyceryl monooleate 2.5 mM 0.89





(mM/dpH).


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Dog FaSSIF: Fasted State Simulated intestinal Fluid.

Table no.10.



2 Sodium taurodeoxycholate 5.0 mM 2.698


4 Lysolecithin 1.25 mM 0.65


6 Sodiumchloride 59.63 mM 0.129

7 Monobasic sodium phosphate 28.65 mM 3.43


Media has a pH of 7.5 and an osmolality of about 181.6+/-4.9mOsmol/kg. and buffer

capacity (mM/dpH) and surface tension 44.8+/-1.1

Dog FaSSGF: Fasted State Simulated gastric Fluid.

Table no.11.



2 Sodium taurodeoxycholate 0.1 mM 0.053


4 Lysolecithin 0.025 mM 0.013


6 Sodiumchloride 18.81 mM 0.04



Media has a pH of 6.5 and an osmolality of about 96.7+/-0.8mOsmol/kg and buffer capacity

(mM/dpH) 10.65+/-0.35 and surface tension 40.7+/-2.4

FaSSCoF

Table no.12


1 Sodium cholate 0.15 mM 0.064



4 Tris 45.4 mM 5.49



(mM/dpH).


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'FeSSCoF': Fed State Simulated Colonic Fluid

Table no.13.

S.No Ingredients Weight in millimoles (mM) Weight in grams

1 Sodium cholate 0.6 0.258

2 Lecithin 0.5 0.378

3 Sodium oleate 0.2 0.06

4 Glucose 77.7 14

5 Tris 30.5 3.69

6 Maleic acid 30.15 3.5

7 Sodium hydroxide 34 1.36


(mM/dpH).

Preparation methods of BRM: As stated above the composition of BRM is varying

depending on the state of GIT we are planning on reproducing for our study. Preparation of

BRM is half completed if we know the composition rest could be achieved only after

preparing the BRM with ideal pH as well as other characterisitics. For this below provided

are methods of preparation of BRM using the given compositions.

1. Preparation of blank Fasted State Simulated Intestinal Fluid (FaSSIF)5

Accurately weighed 1.74g of Sodium hydroxide pellets, 19.77g of Sodium dihydrogen

orthophosphate, and 30.93g of Sodium chloride dissolve in 5 L of purified water and adjust

the pH 6.5 exactly by using 1N Hydrochloric acid.

Preparation of FaSSIF: Accurately weighed 3.3g of sodium taurocholate dissolved in

500mL blank FaSSIF solution, added 11.8mL of a solution to 100mg/mL lecithin in

methylene chloride, and forming an emulsion. The methylene chloride was eliminated under

vacuum at 40°C. Then draw a vacuum for 15minutes at 250mbar and also followed by

15minutes at 100mbar. These results gave in a clear, micellar solution, having no perceptible

odor for methylene chloride. After that it was cool to room temperature and adjusted the

volume upto 2L with blank FaSSIF.

Preparation of blank FeSSIF[6]

Dissolve 20.2 g of NaOH (pellets), 43.25 g of glacial acetic acid, and 59.37 g of NaCl in 5 L

of purified water. Adjust the pH to exactly 5.0 using 1 N NaOH or 1 N HCl.


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Preparation of FeSSIF: Dissolve 16.5 g of sodium taurocholate in 500 mL of blank FeSSIF.

Add 59.08 mL of a solution containing 100 mg/mL lecithin in methylene chloride, forming

an emulsion. The methylene chloride is eliminated under vacuum at about 40°C. Draw a

vacuum for fifteen minutes at 250 mbar, followed by 15 minutes at 100 mbar. This results in

a clear to slightly hazy, micellar solution having no perceptible odor of methylene chloride.

After cooling to room temperature, adjust the volume to 2 L with blank FeSSIF. For

dissolution tests a volume of 500 mL is recommended.[4,5]

BRM can also be prepared without Methylene chloride[7]

Dissolution Media Preparation Conventional FaSSIF and FeSSIF were prepared as per the

literature.

FeSSIF and FaSSIF contain natural surfactants that form more complex lipid aggregates.

Methods of preparing biorelevant media involve emulsification in methylene chloride or

sequential addition. The conventional preparation methods for FeSSIF and FaSSIF are time

consuming and require organic solvents; residual organic solvents, if present in media, may

affect physicochemical properties and dissolution behaviour.

Preparation of Blank FaSSIF pH 6.5: Sodium hydroxide pellets (1.74 g), 19.77 g of

sodium dihydrogen phosphate monohydrate or 17.19 g of anhydrous sodium dihydrogen

phosphate, and 30.93 g of sodium chloride were dissolved in 5 L of purified water. The pH

was adjusted to exactly 6.5 using 1 N sodium hydroxide or 1 N HCl. Preparation of FaSSIF

pH 6.5 Sodium taurocholate (16.5 g) was dissolved in 2000 mL of blank FaSSIF buffer

solution. Lecithin (6.1 g) was added slowly with vigorous stirring by a homogenizer at about

4000 rpm for approximately 30 min or until the solution became clear. After the solution

became clear, it was diluted to 10 L with blank FaSSIF.

Fig. 2 Mean dissolution profiles of dexlansoprazole capsules in FaSSIF media prepared

without methylene chloride (DCM) on different days.


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Preparation of Blank FeSSIF pH 5.0: Sodium hydroxide pellets (44 g) dissolved in 87 mL

of glacial acetic acid and 118.8 g of sodium chloride were added to 10 L of purified water.

The pH was adjusted to exactly 5.0 using 1 N sodium hydroxide or 1 N HCl. Preparation of

FeSSIF pH 5.0 Sodium taurocholate (82.5 g) was dissolved in 2000 mL of blank FaSSIF

buffer solution, and then 29.5 g of lecithin was added slowly with vigorous stirring by a

homogenizer at about 4000 rpm for approximately 45 min or until the solution became clear.

After the solution became clear, it was diluted to 10 L with blank FeSSIF.[1]

Preparation of 1 L BRM by using FaSSIF, FeSSIF or FaSSGF instant powder[4]

To make 1L FeSSIF

1) Preparation of blank buffer

In about 0.9 L of purified water dissolve:4.04 g of Sodium hydroxide pellets+8.65 g of

Glacial acetic acid+11.87 g of Sodium chloride.

2) Check pH

Adjust the pH to 5 with Sodium hydroxide 1N or Hydrochloric acid 1N. Make up to volume

(1 L) with purified water at room temperature.

3) Add powder

Add 11.2 g of FaSSIF / FeSSIF / FaSSGF powder to about 0.5 L of buffer. Stir until powder

is completely dissolved. Make up to volume (1 L) with buffer at room temperature.

To make 1 L of FaSSGF

1) Prepare buffer

In about 0.9 L of purified water dissolve: 2 g of Sodium chloride.

2) Check pH

Adjust the pH to 1.6 with Hydrochloric acid 1N.

Make up to volume (1 L) with purified water at room temperature.

3) Add powder

Add 0.06 g of FaSSIF / FeSSIF / FaSSGF powder to about 0.5 L of buffer.

Stir until powder is completely dissolved.

Make up to volume (1 L) with buffer at room temperature.


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To make 1 L of FaSSIF.

1) Prepare buffer

In about 0.9 L of purified water dissolve

0.42 g of Sodium hydroxide pellets

4.47 g of Sodium phosphate monobasic dihydrate

6.19 g of Sodium chloride.

2) Check pH

Adjust the pH to 6.5 with Sodium hydroxide 1N or Hydrochloric acid 1N.

Make up to volume (1 L) with purified water at room temperature.

3) Add powder

Add 2.24 g of FaSSIF / FeSSIF / FaSSGF powder to about 0.5 L of buffer.

Stir until powder is completely dissolved.

Make up to volume (1 L) with buffer at room temperature.

Selection of Media for the study of a drug profile[8]

To choose the correct media one should know the complete characteristic nature of the

solubility of drug. One should investigate a drug at 2 or more conditions of GIT. Such tests

must determine the nature of solubility of drug all through the GIT. Table Below depicts an

example for one such composition.

Table.14 Test Media that Can Be Used for Solubility Profiling

S.No Test Media pH GI Segment

Standard media

1 SGFsp (USP)a 1.2 Stomach (fasted)

2 SGFsp mod.b 1.6/1.8 Stomach (fasted)

3 Acetate buffer 5.0 Stomach (hypoacidic)

4 Blank FaSSIFc 6.5 Upper small intestine (fasted)

5 Blank FeSSIFc 5.0 Upper small intestine (fed)

6 Acetate buffera 4.5 Upper small intestine

7 SIFsp (USP)a 6.8 Mid small intestine

Additional Media

1 FaSSGF 1.6 Stomach (fasted)

2 Milk 6–7 Stomach (fed)

3 FaSSIF 6.5 Upper small intestine (fasted)

4 FeSSIF 5.0 Upper small intestine (fed)

aBCS conform test media,

bpH-modified,

cContains no bile components, SGFsp simulated

gastric fluid sine pepsin, SIFsp simulated intestinal fluid sine pancreatin, FaSSGF fasted


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state simulating gastric fluid, FaSSIF fasted state simulating gastric fluid, FeSSIF fed state

simulating gastric fluid, Blank FaSSIF fasted state simulating gastric fluid without bile

compounds, Blank FeSSIF fed state simulating gastric fluid without bile compounds.

To classify the API according to the biopharmaceutics classification scheme (BCS)[9]

this set

of media also covers the three BCS conform test media required for solubility and dissolution

experiments. For the solubility profiling of drugs formulated in IR formulations, conditions of

the upper GI tract, which are listed in Table IV, are sufficient. For the characterization of

drugs formulated in modified release dosage forms, additional media to simulate the lower

small intestine (pH 7–7.5) and the proximal colon (pH 5–6) should be added.[10,11]

Subsequent to the solubility experiments, the dose/solubility ratio (D/S) should be calculated

according to the BCS. Whereas a D/S > 250 ml in aqueous media indicates solubility issues

in the corresponding GI segment(s), a D/S < 250 ml at all pH values of interest indicates that

dissolution is very unlikely to limit drug absorption. If the D/S is >250 ml but in the range of

250 to 1,000 ml in all aqueous buffers, solubility experiments should also be performed in

biorelevant media (see “additional media” in Table IV). Particularly for lipophilic compounds

where wetting problems can occur, physiological concentrations of bile salts may enhance

wetting or may solubilize the drug and thus help overcome the solubility issues observed in

simple buffers. For drugs having a D/S higher than 1,000 ml, bile components are unlikely to

overcome all solubility problems. For such drugs, special formulation technologies are

required. These can include material engineering like the micronization of the API, chemical

modifications like salt formation, and a couple of other formulation strategies, e.g., solid

dispersions, cyclodextrin complexes, or lipid formulations.[12]

CONCLUSION

The development of Biorelevant dissolution medium mainly used as in vitro surrogate for in

vivo performance. Buffer is unable to simulate the dissolution as that of in-vivo so that bio

relevant medium has been developed. This review providing information regarding different

types and composition of Biorelevant media and preparation methods.

REFERENCES

1. https://biorelevant.com/blog/what-is-in-vitro-in-vivo-correlation-ivivc/.

2. Shono, et al., European Journal of Pharmaceutics and Biopharmaceutics, 2009; 73:

107-114.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2895438/table/Tab4/

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3. http://www.softschools.com/formulas/chemistry/moles_to_grams_conversion_formula/11

1/.

4. https://biorelevant.com/biorelevant-media-types/.

5. RP-HPLC Method for the Simultaneous Estimation of Cilnidipine and Metoprolol

Succinate in Bulk and Tablet dosage form in BRM (FaSSIF) Madhukar A1, 2*, N.

Kannappan2.

6. http://www.dissolutiontech.com/DTresour/200405Articles/DT200405_A03.pdf.

7. http://www.dissolutiontech.com/DTresour/201402Articles/DT201402_A05.pdf.

8. Sandra Klein, The use of Biorelevant Dissolutionn media to forecast the In-Vivo

performance of a drug, AAPS J., 2010 Sep; 12(3): 397–406.

9. Amidon GL, Lennernas H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic

drug classi?cation: the correlation of in vitro drug product dissolution and in vivo

bioavailability. Pharm Res., 1995; 12(3): 413?20.

10. Sandra Klein, The use of Biorelevant Dissolutionn media to forecast the In-Vivo

performance of a drug, AAPS J., 2010 Sep; 12(3): 397–406.

11. Klein S. Biorelevant dissolution test methods for modified release dosage

forms.Frankfurt: Shaker, 2005.

12. Stegemann S, Leveiller F, Franchi D, de Jong H, Linden H. When poor solubility

becomes an issue: from early stage to proof of concept. Eur J Pharm Sci., 2007; 31(5):

249–2461. doi: 10.1016/j.ejps.2007.05.110. [PubMed] [Cross Ref].

http://www.softschools.com/formulas/chemistry/moles_to_grams_conversion_formula/111/

http://www.softschools.com/formulas/chemistry/moles_to_grams_conversion_formula/111/

https://biorelevant.com/biorelevant-media-types/

http://www.dissolutiontech.com/DTresour/200405Articles/DT200405_A03.pdf

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2895438/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2895438/

https://www.ncbi.nlm.nih.gov/pubmed/17616376

https://dx.doi.org/10.1016%2Fj.ejps.2007.05.110

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