![3. DISSOLUTION
• It is process in which solid substance solubilises in given solvent i.e.
mass transfer from solid surface to liquid phase.
• Using USP apparatus I at 100 rpm or USP apparatus II at 50 rpm .
• Dissolution Media [900 ml],
1. 0.1 N HCl or simulated gastric fluid (pH 1.2)
without enzyme.
2. pH 4.5 buffer & pH 6.8 buffer.
3. Simulated intestinal fluid without enzyme
Compare dissolution profiles of test and reference products using a
similarity factor (f2).
9](https://image.slidesharecdn.com/pe-2020-305biopharmaceuticalclassificationsystem-210813083424/85/Biopharmaceutical-Classification-System-9-320.jpg)
Biopharmaceutical Classification System
- 1. BIOPHARMACEUTICAL CLASSIFICATION SYSTEM (BCS) Presented By:- Vaishnavi A. Bhosale M.S. Pharmaceutics ( 1st Semester) NIPER Hyderabad 1
- 2. CONTENTS: • Introduction • Objectives of BCS • Factors affecting BCS Classification • Classes of BCS • Applications • Bio wavers • Limitations of BCS • Extensions to BCS • Conclusion 2
- 3. INTRODUCTION • BCS is a scientific framework for classifying drugs based on their AQUEOUS SOLUBILITY, INTESTINAL PERMEABILITY and DISSOLUTION RATE • The fundamental basis established by Dr. Gordon Amidon • First introduced into the regulatory decision making process in the guidance document on Immediate Release Solid Oral Dosage forms for Scale up and Post Approval changes. 3 What is the need for classification based on biopharmaceutics of drug ? It is important in determining Bioavailability
- 4. • The principle of the BCS is that if two drug products yield the same concentration profile along the GIT , they will yield the same plasma profile after oral administration. This can be summarized by the following: where, J is the Flux across the gut wall Pw is the the permeability of the gut wall to the drug Cw is the concentration profile at the gut wall 4 J = Pw Cw
- 5. OBJECTIVES OF BCS:- • To identify the challenges of formulation Design. • To guide decisions w.r.t. IVIVC. • To improve the efficiency of drug development and identifying expendable clinical bioequivalence tests. • To explain when a waiver for in vivo bioavailability and bioequivalence may be requested. • To assist in QC in SUPAC. • To recommend a class of immediate-release (IR) solid oral dosage forms for which bioequivalence may be assessed based on in vitro dissolution tests. • To recommend methods for classification according to dosage form dissolution along with the solubility-permeability characteristics of the drug product. 5
- 6. FACTORS AFFECTING BCS :- • The Biopharmaceutical Classification System has been developed to provide a scientific approach to follow for prediction of in vivo pharmacokinetics of oral immediate release (IR) drug product by classifying drug based on:- 6 1. SOLUBILITY 3. DISSOLUTION RATE 2. PERMEABILITY
- 7. 1. SOLUBILITY • The maximum amount of solute dissolved in a given solvent under standard conditions of temperature, pressure and pH. • Solubility is the ability of the drug to be solution after dissolution • A drug substance is classified as ‘HIGHLY SOLUBLE’ if the highest single therapeutic dose is completely soluble in 250 ml or less of aqueous media over the pH range of 1.0 – 7.5 at 37 ± 1°C • Methods for determination of solubility 1. Miniaturized shake-flask method 2. Semi-automated Potentiometric acid/base titrations 3. A computational screening model 4. Miniature device 7
- 8. 2. PERMEABILITY • Permeability of the drug to pass the biological membrane. • Permeability is indirectly based on the extent of absorption of a drug substance . • Drug substance is considered to be ‘HIGHLY PERMEABLE’, when the extent of absorption in human determined to be 90% or more of administered drug or compare to in vivo reference dose. • Determination of permeability A. HUMAN PHARMACOKINETIC STUDIES • Mass balance studies • Absolute bioavailability studies B. INTESTINAL PERFUSION METHODS In vivo or in situ intestinal perfusion in a suitable animal model. In vitro permeability methods using excised intestinal tissues In vitro permeation studies across a monolayer of cultured epithelial cells . e.g. Caco-2 cells or TC-7 cells 8
- 9. 3. DISSOLUTION • It is process in which solid substance solubilises in given solvent i.e. mass transfer from solid surface to liquid phase. • Using USP apparatus I at 100 rpm or USP apparatus II at 50 rpm . • Dissolution Media [900 ml], 1. 0.1 N HCl or simulated gastric fluid (pH 1.2) without enzyme. 2. pH 4.5 buffer & pH 6.8 buffer. 3. Simulated intestinal fluid without enzyme Compare dissolution profiles of test and reference products using a similarity factor (f2). 9
- 10. 10 Sr. No. Dimensionless Parameter Ratio of Ideally should be Indicative of 1. Absorption Number (An) Mean Residence time in G.I.T./ Mean absorption time An > 1 G.I. Permeability to drug substance 2. Dissolution Number (Dn) Mean Residence Time / Mean Dissolution Time Dn > 1 Drug Release from the formulation 3. Dose Number (Do) (Highest dose/ Volume) / Solubility Do < 1 Solubility of the drug substance This classification is associated with drug dissolution and absorption model, which identifies the key parameters controlling drug absorption as a set of dimensionless numbers.
- 11. CLASSES OF BCS 11 CLASS I High Solubility High Permeability 35 % ( in market) 25 % ( NCE) CLASS III High Solubility Low Permeability 25 % (in market) 5 % ( NCE) CLASS II Low Solubility High Permeability 30% (in market) 70% (NCE) CLASS IV Low Solubility Low Permeability 10% (in market) 20% ( NCE)
- 12. CLASS I DRUGS • The drugs of this class exhibit high absorption number and high dissolution number. • For those class 1 drugs formulated as IR products, dissolution rate generally exceeds gastric emptying. • Behave like an oral solution in-vivo. • The rate-limiting step is gastric emptying. • These compounds are well absorbed. • Absorption rate is usually higher than the excretion rate. • E.g. Amiloride, Metaprolol, paracetamol etc 12
- 13. CLASS II DRUGS • The drugs of this class have a high absorption number but a low dissolution number. • In vivo drug dissolution is then a rate-limiting step for absorption except at a very high dose number. • The absorption for Class II drugs is usually slower than for Class I and occurs over a longer period of time. • The bioavailability of these products is limited by their solvation rates. • Hence, a correlation between the in vivo bioavailability and the in vitro solvation can be found. • E.g. Ritonavir, Tamoxifen, Glibenclamide, etc 13
- 14. SUBCLASSES OF CLASS II • Basis- significant impact of pKa on the solubility and dissolution of drugs. • BCS Class II drug product dissolution in vitro as well as in vivo is highly dependent on acidic or basic nature of drug. • Hence, the class II drugs are sub classified as: 14 CLASS II a Weakly acidic drugs pKa ≤ 5 CLASS II b Weakly basic drugs pKa ≥ 6 CLASS II c Neutral Drugs
- 15. SUB CLASSES OF CLASS II • Class II a Drugs • Drugs are insoluble at gastric pH & soluble at intestinal pH • At intestinal pH (~6.5), the dissolution would increase upto 100 times • Hence, dissolution rate would be faster than gastric emptying rate • Thus, these drugs reflect gastric emptying and luminal pH differences. • Examples- ibuprofen and ketoprofen CLASS II b DRUGS • Exhibit high solubility and dissolution rates at acidic pH in stomach • May precipitate in intestinal pH • Examples- carvedilol and ketoconazole CLASS II c DRUGS • Solubility is not affected by in vivo pH change • Example- fenofibrate and danazole 15
- 16. CLASS III DRUGS • Drug permeability is the rate-limiting step for drug absorption, but the drug is solvated very quickly. • These drugs exhibit a high variation in the rate and extent of drug absorption. • Since the dissolution is rapid, the variation is attributable to alteration of physiology and membrane permeability rather than dosage form factors. • E.g. Lisinopril, Atenolol, Cimetidine, etc • CLASS IV DRUGS • The drugs of this class are problematic for effective oral administration. • These compounds have poor bioavailability. • They are usually not well absorbed through the intestinal mucosa, and a high variability is expected. • E.g. Taxol, Griseofulvin, etc 16
- 17. APPLICATIONS • Application in early drug development and then in the management of product change through its life cycle • Aids fundamental understanding of the biopharmaceutical and physical properties of the drug • Aids discriminatory dissolution method development • Can help guide the development of in-vitro/in-vivo correlations • Can be used to obtain a biowaiver • Development of poorly soluble drugs 17
- 18. Applications of BCS in Oral Drug Delivery system CLASS I DRUGS. • Achieve a target release profile associated with a particular pharmacokinetic and/or pharmacodynamic profile. • Formulation approaches include both control of release rate and certain physicochemical properties of drugs like pH-solubility profile of drug • Pregabalin is a BCS Class 1 compound (highly permeable and highly soluble). Pregabalin is an amino acid and its lowest aqueous solubility occurs at its isoelectric point (at pH 7.4). It is considered high solubility as the amount of water needed (<10 mL) to dissolve the highest dose strength (300 mg) at pH 7.4 is less than the 250 mL criteria. Pregabalin meets the BCS criteria for a highly permeable compound as greater than 90% of the dose is excreted unchanged in the urine CLASS II DRUGS • Micronisation 18
- 19. • Addition of surfactants • Solid dispersions • Salt Formation • Formulation as emulsions and microemulsions systems • Use of complexing agents like cyclodextrins • Solid dispersions of ezetimibe were prepared by melt extrusion method using Kollidon VA64 as carrier. Solid dispersions have exhibited very high solubility in pH 4.5 acetate buffer than the other buffer media. The ezetimibe drug content in all the dispersions were found to be in the range of 99.6 to 99.76 %. CLASS III DRUGS • Require the technologies that address to fundamental limitations of absolute or regional permeability. • Peptides and proteins constitute the part of class III and the technologies handling such materials are on rise now days 19
- 20. The different formulation strategies for enhancement of oral bioavailability of BCS class III drugs over here is categorized into (a) formulations imparting lipophilic character to drug and (b) formulations that increase gastric retention time of drug. Double emulsion Niosomes CLASS IV DRUGS • Major challenge for development of drug delivery system and the route of choice for administering such drugs is parenteral (solubility enhancers.) • Hydrochlorothiazide (HCTZ)7 which is a well categorized • Thiazide diuretic, considered as the first-line of treatment for hypertension and listed as an essential medicine in WHO list. Although, it’s an essential medication but due to its low bioavailability (65%) low permeability9 and extensive hepatic metabolism, it loses its therapeutic efficacy. Hence, to evade all these limitations an up graded delivery mechanisms are required which can be attained by designing the polymer based nanoparticle drug delivery system. 20
- 21. 21
- 22. BIOWAVER • A BIOWAIVER is an exemption from conducting human bioequivalence studies when the active ingredient(s) meet certain solubility and permeability criteria in vitro and when the dissolution profile of the dosage form meets the requirements for an "immediate" release dosage form. • PREREQUISITES FOR BIO WAVER ( ICH M9 guideline) • Rapid and similar dissolution. • High solubility & High permeability. • Wide therapeutic window. • Excipients used in dosage form used previously in approved IR solid dosage forms. 22
- 23. REQUEST FOR BIOWAVER Data Supporting Rapid and Similar Dissolution Data supporting High Permeability Data supporting High Solubility Dissolution data obtained with 12 individual units of the test and reference products at each specified testing interval for each individual dosage unit. A graphic representation of the mean dissolution profiles for the test and reference products in the three media. · Data supporting similarity in dissolution profiles between the test and reference products in each of the three media, using the f2 metric. For direct permeability methods, information supporting method suitability with a description of the study method, criteria for selection of human subjects, animals, or epithelial cell line, drug concentrations, description of the analytical method, method to calculate extent of absorption or permeability, and information on efflux potential (if appropriate). Description of test methods (analytical method, buffer composition). · Information on chemical structure, molecular weight, nature of drug substance, dissociation constants. · Test results summarized in a table with solution pH, drug solubility, volume to dissolve highest dose strength. · Graphical representation of mean pH-solubility profile 23
- 24. 24 ACCEPTANCE REJECTION • Immediate release, solid orally administered dosage forms or suspensions designed to deliver drug to the systemic circulation • Where the drug substances exhibit high solubility and, either high permeability (BCS Class I) or low permeability (BCS Class III) • When the drug substances in test and reference products are identical even if they contain different salts provided that both belong to BCS Class I (high solubility and high permeability). • Drug products having a narrow therapeutic index • When the test product contains a different ester, ether, isomer, mixture of isomers, complex or derivative of a drug substance from that of the reference product, since these differences may lead to different bio availabilities . •Drug products with buccal or sublingual absorption ELIGIBILITY CRITERIA FOR BIOWAVER
- 25. EXCIPIENTS INCLUDED • Ideally, the composition of the test product should mimic that of the reference product. • However, where excipient differences exist, they should be assessed for their potential to affect in vivo absorption. • This should include consideration of the drug substance properties as well as excipient effects. • To be eligible for a BCS-based biowaiver, the sponsor should justify why the proposed excipient differences will not affect the absorption profile of the drug substance under consideration, i.e., rate and extent of absorption, using a mechanistic and risk-based approach. 25
- 26. LIMITATIONS OF BCS • Effects of Food, Absorptive transporters, Efflux transporters & Routes of elimination(renal/biliary) are important determinants of BA for immediate release oral dosage forms, which are not considered in BCS. • Limitations of BCS as a Predictor of Drug Disposition • Permeability (90% absorption) is difficult to determine, and difficult to convince the regulatory agency . • There is little predictability for BCS classification drugs beyond Class 1 primarily due to the difficulty of • determining and proving 90% absorption, many drugs are misclassified (e.g. HIV protease inhibitors as Class 4 compounds). 26
- 27. EXTENSIONS TO BCS 1. Six class BCS: • The drugs are classified into six classes. • The solubility was classified as “low” or “high” permeability was allotted as “low” “intermediate” or “high”. 2. Quantitative BCS (QBCS): • Quantitative BCS (QBCS) was developed using the dose: solubility ratio as core parameter for classification. • States that solubility is a static equilibrium parameter and cannot describe the dynamic character of the dissolution process for the entire dose administered. 27
- 28. 3. Pulmonary BCS • The BCS is limited to the gastrointestinal tract. • The pulmonary BCS (PBCS) consider the specific biology of the lung as well as particle deposition, aerosol physics, and the subsequent processes of drug absorption and solubility 4. BDDCS CLASSIFICATION • BDDCS (Biopharmaceutical Drug Disposition and Classification System) divides compounds into four classes based on their permeability and solubility. • This classification system is useful in predicting effects of efflux and uptake transporters on oral absorption as well as on post absorption systemic levels following oral and intravenous dosing. 28
- 29. BDDCS 29
- 30. CONCLUSION • BCS aims to provide a regulatory tool for replacing certain BE studies by accurate in vitro dissolution tests. • This increased awareness of a proper biopharmaceutical characterization of new drugs may in the future result in drug molecules with a sufficiently high permeability, solubility and dissolution rate and that will automatically increase the importance of the BCS as a regulatory tool over time 30
- 31. REFERENCES • Brahmankar, D. M and Jaiswal, Sunil. B (2009). Biopharmaceutics and Pharmacokinetics – A Treatise. 2nd edition. Vallabh Prakashan, Page no. 27-29 and 332 - 335. • Leon shargel, Susanna wu-pong, Andrew B.C.Yu , Applied Biopharmaceutics & Pharmacokinetics, 5th edition 2005, published by the Mc Graw hills companies, page no. 431-436 & 482-484. • Wagh M.P, Patel J.S., 2010, International Journal of Pharmacy and Pharmaceutical Sciences, Vol 2, Page 12-19 • SV Deshmane, PP Chinchole, RM Gaurkhede, MA Channawar, AV Chandewar. The Biopharmaceutics Classification System: A Review. Research J. Pharm. and Tech. 2(1): Jan.- Mar. 2009; Page 8-11 • General Notes on Biopharmaceutics Classification System (BCS)- based Biowaiver Applications by WHO • ICH M9 Guideline. • Ghadi R, Dand N. BCS class IV drugs: Highly notorious candidates for formulation development. J Control Release. 2017 Feb 28;248:71-95 • Ashis kumar mehatha, vidyadhara Suryadevara*, sasidhar R lankapalli , abhijit M deshmukh, laxmana p sambath , 2014, turk j pharm sci, formulation and optimization of ezetimibe containing solid dispersions using kollidon VA64, 113-126 • Pregabalin zentiva assessment report (EMEA) 31