Biopharmaceutics Classification System (BCS)

Presented By: Nidhi Jasani O9MPH505 Nirma University

Guided By: Miss Shital Baria Mrs Renuka Mishra1

CONTENTS

Introduction BCS: Rationale Classification Class Boundaries Solubility Determination Method Permeability Determination Dissolution determination Biowaver Reference2

INTRODUCTIONThe

Biopharmaceutics Classification System is a guidance for predicting the intestinal drug absorption provided by the U.S. Food and Drug Administration .

The

solubility classification is based on a United States Pharmacopoeia (USP) aperture. intestinal permeability classification is based on a comparison to the IV route.

The

BCS provide a scientific approach that takes in to account three major factors that govern the rate and extent of drug absorption from Immediate Release (IR) oral solid dosage form - Solubility - Intestinal

permeability - Dissolution

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AIM OF BCS GUIDANCE

To provide regulatory tool for replacing certain bioequivalence studies by accurate in-vitro dissolution tests. This will reduce the cost in drug development process, also reduce unnecessary drug exposure in healthy objects. To provide guidance for industry.

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BCS: RationaleThe major steps occurring during oral drug absorption in serial order are 1. The dissolution of the drug from the dosage form 2. The solubility of drug as a function of its physicochemical characteristics 3. The drugs effective permeability to the intestinal mucosa 4. Its presystemic metabolism

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CLASSIFICATIONAccording to the BCS, drug substances are classified as follows: Class I - High Permeability, High Solubility Class II - High Permeability, Low Solubility Class III - Low Permeability, High Solubility Class IV - Low Permeability, Low Solubility

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CLASS BOUNDARIESHighly soluble when highest dose strength is soluble in 250 ml or less water over a pH range of 1 to 7.5

Highly when extent of intestinal absorption is 90 % or permeable higher based on mass-balance determination or in comparison to IV reference dose Rapidly dissolving when not less than 85% of labeled amount of drug substance dissolves within 30min using USP apparatus I at 100 rpm in volume of 900 ml or less in each of following media (1)0.1 N HCL or simulated gastric fluid without enzymes. (2)4.5 pH buffer (3)6.8 pH buffer or simulated intestinal fluid 9 USP without enzymes.

SOLUBILTY DETERMINATIONBy pH solubility profile of test drug in aqueous media with a pH range of 1 to 7.5 Shake flask or titration method. Analysis by validated stability indicating assay.

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PERMEABILITY DETERMINATION Extent of absorption in humans: Mass-balance pharmacokinetic studies.

Using unlabeled, stable isotopes or a radio labeled drug substances can used to document the extent of absorption of a drug. Absolute bioavailability studies. Oral BA determination using IV administration as a references can be used. Depending on the variability of the studies, a sufficient number of subject should be enrolled to provide a reliable estimate of extent of absorption. When the absolute BA of a drug is shown to be 90% or more, additional data to document drug stability in the gastrointestinal fluid is not necessary. 11

Intestinal

permeability methods:

-In -vivo intestinal perfusions studies in humans. -In vivo or In-situ intestinal perfusion studies in animals. -In -vitro permeation experiments with excised human or animal intestinal tissue. -In-vitro permeation experiments across epithelial cell monolayer (e.g. CaCo-2 cell)Partition coefficient The partition coefficient is a ratio of concentrations of unionized compound between the two solutions. To measure the partition coefficient of ionizable solutes, the pH of the aqueous phase is adjusted such that the predominant form of the compound is un-ionized.12

The logarithm of the ratio of the concentrations of the un-ionized solute in the solvents is called log P

Ex: acetaminophen 0.51 caffeine -0.07 ibuprofen 3.5

In-vivo or In-situ animal models and In-vitro methods , such as those using cultured monolayers of animal or human epithelial cells, are considered appropriate for passively transported drugs.

For In-vivo intestinal perfusion studies in humans, 6 models drugs are recommended.

For In-vivo or In-situ intestinal permeability in animals and For In-vitro culture methods, 20 model drugs are recommended.

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DISSOLUTION DETERMINATION

USP apparatus I (basket) at 100 rpm or USP apparatus II (paddle) at 50 rpm. Dissolution media (900 ml): 0.1 N HCl or simulated gastric fluid, pH 4.5 buffer, and pH 6.8 buffer or simulated intestinal fluid. Compare dissolution profiles of test and reference products using a similarity factor (f2).

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KEY PARAMETERS CONTROLLING DRUG ABSORPTION

Absorption number (An), defined as the ratio of the mean residence time to mean absorption time. Dissolution number (Dn), defined as the ratio of mean residence time to mean dissolution time. Dose number (D0), defined as the mass (Dose) divided by the product of uptake volume (250 ml) and solubility of drug. D0 = Dose/(V.Cs)16

CLASS I

High absorption number and high dissolution number RLF(Rate limiting factor) : Drug dissolution : Gastric emptying rate (if dissolution is rapid) It consist of water soluble drugs that are well absorbed from GIT and have preferred physicochemical properties e.g. Metoprolol, Diltiazem, Verapamil, Propranolol17

CLASS II

High absorption number but low dissolution number RLF: In-vivo drug dissolution except at a very high dose It consists of water insoluble drugs which when dissolved are well absorbed from GIT Absorption is usually slower than Class I and takes place over a longer period of time The limitation can be equilibrium or kinetic in nature. e.g. Phenytoin, Danazol, Ketoconazole, Mefenamic acid, Nifedinpine.18

CLASS III

High dissolution number and low absorption number RLF: In-vivo permeability Since the dissolution is rapid, the variation is attributable to alteration of physiology and membrane permeability rather than the dosage form factors. It consists of water soluble drugs that do not readily permeate biomembranes e.g. Cimetidine, Acyclovir, Neomycin B, Captopril.19

CLASS IV

Low dissolution and low absoption number Class IV drugs exhibit a lot of problems for effective oral administration It consist of water insoluble drugs which when solubilized do not readily penetrate biomembranes class 4 compounds are rarely developed and reach market. Nevertheless a number of class IV drugs do exist. e.g. Taxol. In vitro- In vivo correlation (IVIVC) is usually excepted for class I and class II drugs.20

Classification of orally administered drugs on the WHO model list according to BCSdrugamiloridechloroquine diazepam digoxine metronidazole phenobarbital

solubilityhighhigh high high high high

permeability dose(mg)highhigh high high high high

BCS classII I I I I

5100 2;5 0.625 200-500 15-100

primaquinecarbamazepin dapsone

highlow low

highhigh high

7.5;15100,200 50,100

III II

griseofulvinibuprofen

lowlow

highhigh

125,250200,400

IIII21

drugnitrofurantoin

solubilitylow

permeability dose(mg)high 100

BCS classII

nifedipineaciclovir

lowhigh

highlow

10200

IIIII

ascorbic acidatenolol captopril chlorampheni col aluminum hydroxide furoseide

highhigh high high low low

lowlow low low low low

5050,100 25 250 500 40

IIIIII III III IV IV

indianavirnelfinavir ritonavir

lowlow low

lowlow low

200,300,400250 100

IVIV IV22

Biowaver

Means to waive off doing bioavailability and bioequivalence studies. Introduction In 1995 Amidon et al. devised a bio-pharmacetics classification system (BCS) to classify drugs based on their aqueous solubility and intestinal permeability It was then recognized that dissolution rate has a negligible impact on bioavailability of highly soluble and highly permeable (BCS Class I) drugs when their formulation's dissolution is sufficiently rapid.23

1. 2. 3. 4. 5.

As a result, various regulatory agencies including the United States Food and Drug Administration (FDA) now allow bioequivalence of formulations of BCS Class I drugs to be demonstrated by in vitro dissolution (often called a bio-waiver). Conditions for justifying request of biowaiver. Drug must be highly soluble & permeable. Must be stable in GIT. Product is designed not to be absorbed in oral cavity. Must not have narrow therapeutic index. Excipients used in IR solid dosage forms must have no significant effect on rate & extent of oral drug absorption . 24

BIOWAVER EXTENSIONS (1) For class II drugs: Here in-vivo dissolution is rate limiting step. If in-vivo dissolution can be estimated in vitro, it is possible to establish IVIVC. But experimental methods are difficult to design & validate because no. of in-vitro process involved. Key determinant for class II drug absorption is the solubility in the absorbing region of intestine. So, change in formulation is required. Add SLS to mimic solubilization in vitro and maintainance of sink condition in vivo resulting from continuous absorption.25

(2) For class III drugs: Drugs shows permeability limited absorption If the dissolution of class III drugs is rapid under all physiological pH conditions, it is expected that they will behave like oral solution in-vivo and in-vivo bioequivalence study is generally waived off for oral solutions For E.g.. Isoniazid which lies at borderline of BCS class I & III. Its biowaiver is recommended when the test product meets WHO requirements for Very rapidly dissolving and contains only excipients commonly used in isoniazid products . Lactose & other deoxidizing saccharides containing formulations should be subjected to in-vivo BE study.[JPS vol.96(3); March 2007]26

QUANTITATIVE VERSION OF BCSRinaki et al. developed a quantitative version of BCS termed as QBCS using Dose/solubility ratio as the key parameter for solubility classification .

*Papp- apparent permeability and q- Dose/solubility27

REFERENCES

www.fda.gov/cder/guidance/. Aukunuru Jithan; Oral Drug Delivery Technology,, pg no:398 Anshu sharma, et al. BCS and Biowaivers: Role in Drug Product Design; Research J Pharm and Tech 1(3) July-Sept 2008 144-151 Nattee Sirisuth and Natalie D. Eddington; In-Vitro-In-Vivo Correlation: Definitions And Regulatory Guidance; International Journal of Generic Drugs William Addicks, Application of the Biopharmaceutical Classification System at a Generic Pharmaceutical Company. Mylan Laboratories Inc. www.tsrlinc.com/index.htm 28