Biopharmaceutical Considerations in Drug Product Design and In Vitro Drug Product Performance

Biopharmaceutical Considerations in Drug Product Design and In Vitro Drug Product Performance

1. Biopharmaceutical Considerations in Drug Product Design and In Vitro Drug Product Performance Presented by – Sushmita Mishra M. Pharm 2 nd sem (Pharmaceutics) Under the Supervision of : Mr. Vikas Srivastava (Assistant Professor) (Department of Pharmaceutics , Goel institute of Pharmacy and Sciences, Lucknow) GOEL INSTITUTE OF PHARMACY AND SCIENCES, LUCKNOW

2. Contents Introduction Aim of biopharmaceutics Biopharmaceutical factors affecting the drug bioavailability Rate limiting steps in drug absorption In vitro :dissolution and release testing In vitro in vivo correlation

3. Introduction Biopharmaceutics is defined as the study of factors influencing the rate and amount of drug that reaches the systemic circulation and the use of this information to optimize the therapeutic efficacy of the drug product. Biopharmaceutics links the physical and chemical properties of drug and drug product to their performance, in-vivo. Aim:- The aim of biopharmaceutics is to adjust the delivery of drug from drug products in a such manner as to provide :optimal therapeutic activity and safety for the patient. A primary concern in biopharmaceutics is the bioavailability of drugs. “ Bioavailability is the assessment the rate and extent at which the active drug becomes available at the site of action .

4. Biopharmaceutics consideration in the design of a drug product : Pharmacodynamic considerations Drug consideration Drug product consideration Patient consideration Manufacturing consideration Pharmacodynamic consideration : Therapeutic objective – Toxic effects Adverse reactions Drug consideration: Chemical & physical properties of drug pKa & pH profile Particle size Polymorphism Partition coefficient Excipient interaction pH stability profile Solubility

5. Drug product consideration : Pharmacokinetic of drug Bioavailability of drug Desired dose of drug Dosing frequency Patient consideration: Compliance & acceptability of drug Cost Manufacturing consideration: Cost Availability of raw materials QC

6. Biopharmaceutical Product Development Scheme DISCOVERY BIOPROCESS DEVELOPMENT ANAL Y TICAL & PREFORMULATION FORMULATION DEVELOPMENT BULK SUBSTANCE NON CLINICAL DEVELOPMENT PRODUCT TOXICOLOGY CLINICAL DEVELOPMENT MARKET

7. Biopharmaceutical factors affecting drug bioavailability There are various factors which affect the bioavailability of drugs - PHARMACEUTICAL FACTORS PATIENT RELATED FACTORS ROUTE OF ADMINISTRATION

8. 1.PHARMACEUTICAL FACTORS Formulation Factors Disintegration time Manufacturing variable – a) Method of granulation b) Compression force Nature and type of dosage form Pharmaceutical ingredient Product age and storage conditions

9. 1. Disintegration time(D.T) : - It is defined as the time taken by the solid dosage form to breakdown into smaller particles in the body after their ingestion. *Order of disintegration of the solid dosage forms : Capsules>tablets >coated tablets>enteric coated tablets >sustained release tablets 2. Manufacturing variable :- a)Method of granulation Wet granulation Direct compression b ) Compression force : Higher compression force yields a tablet with greater hardness and reduced wettability and hence have a long D. T. 3. Nature and type of dosage form: D epending upon the nature and type of dosage form, the absorption pattern of a drug decreases in the following order; Solutions >emulsions > suspensions >capsules >tablets >coated tablets >enteric coated tablets>sustained release tablet

10. 4. Pharmaceutical ingredients: More the no. o f excipients in dosage form, more complex it is & greater the potential for absorption and bioavailability problems. Vehicle Diluents Binding agents Disintegrating agents 5. Product age and storage conditions : A lterations in storage conditions and prolonged duration of storage of drug products may modify their physicochemical properties resulting in altered drug absorption pattern .

11. 2.PATIENT RELATED FACTORS Age Gastric emptying Intestinal transit Diseases Effects of food Blood flow to GIT First pass metabolism

12. 3.ROUTE OF ADMINISTRATION Parenteral Oral Topical Rectal Inhalation It’s expected that bioavailability of drugs to be in this order - Parenteral >Oral>Rectal >Topical

13. Rate Limiting Step in drug absorption In a series of kinetic or rate processes, the rate at which the drug reaches the systemic circulation is determined by the slowest of the various steps involved in the sequence. Such a step is called as the rate-determining or rate-limiting step. Systemic drug absorption from a drug product consists of a succession of rate processes. For solid oral, immediate release drug products ( eg : tablets, capsules) the rate processes include Disintegration of drug product and its release Dissolution of drug in aqueous environment Absorption across cell membranes into systemic circulation Drug in drug product Drug in solution Drug in body Disintegration release Dissolution Absorption Solid drug particles Rate processes of drug bioavailability

14. Biopharmaceutical classification system (BCS) For highly soluble and highly permeable drugs. In general, the disintegration test serves as a component in the overall quality control of tablet manufacture. Class Solubility Permeability Absorption Pattern Rate-limiting step in Absorption Drug example I High High Well absorbed Gastric emptying Diltiazem II Low High Variable Dissolution Nifedipine III High Low Variable Permeability Insulin IV Low Low Poorly absorbed Case by case Taxol

15. Dissolution Dissolution is the process by which a solid drug substance becomes dissolved in a solvent. The steps in dissolution include the process of drug dissolution at the surface of the solid particle, thus forming a saturated solution around the particle. The dissolved drug in the saturated solution, known as the stagnant layer, diffuses to the bulk of the solvent from regions of higher drug concentration to regions of low drug concentration.
The overall rate of drug dissolution may be described by the Noyes-Whitney equation dc/ dt =AD/h(Cs-C) Where, dc/ dt = rate of drug dissolution at time t D = diffusion rate constant. A = surface area of the particle Cs = concentration of drug in the stagnant layer C = concentration of drug in the bulk solvent h = thickness of the stagnant layer

16. This equation   shows that dissolution in a flask may be influenced by the physicochemical characteristics of the drug, formulation and solvent.  The dissolution of drug in the body, particularly in the gastrointestinal tract, is considered to be dissolving in an aqueous environment. Permeation of drug across the gut wall is affected by the ability of the drug to diffuse and to partition between the lipid membranes. A favourable partition coefficient (K oil/water) will facilitate drug absorption. Drug in particle form Drug in solution form Drug in blood stream Permeation is rate limiting step for hydrophilic drugs. E.g.,Neomycin Dissolution is rate limiting steps for lipophilic drugs e.g.,Griseofulvin

17. In Vitro :dissolution and drug release testing Dissolution and drug release tests are in-vitro tests that measure the rate and extent of dissolution or release of the drug substance from a drug product , usually in an aqueous medium under specified conditions. The dissolution test is an important quality control procedure for the drug product and is often linked to product performance in vivo. In-vitro drug dissolution studies are most often used for monitoring drug product stability and manufacturing process. Conditions that May Affect Drug Dissolution and Release: Drug and formulation related 1.Drug substance Particle size Polymorph Surface area Chemical stability in dissolution media 2. Formulation of drug product Excipients (lubricants, suspending agents, etc.)

18. Compendial methods of dissolution : The United States Pharmacopeia (USP) provides compendial methods for dissolution testing that are widely used in the pharmaceutical industry to ensure the quality and consistency of drug products. However, there are also alternative methods of dissolution testing that can be used to complement or supplement the compendial methods. The USP-NF describes the official dissolution apparatus and includes information for performing dissolution tests on a variety of drug products including tablets, capsules, and other special products such as transdermal preparations. The selection of a particular dissolution method for a drug may be specified in the USP-NF monograph for a particular drug product or may be recommended by the FDA.

19. USP-NF and non-USP-NF Dissolution apparatus Apparatus Name Agitation method Drug product Apparatus 1 Rotating basket Rotating stirrer Tablets, Capsules Apparatus 2 Paddle Rotating stirrer Tablets, Capsules, modified drug product, suspension Apparatus 3 Reciprocating cylinder Reciprocation Extended-release drug products Apparatus 4 Flow cell Fluid movement Drug products containing low water-soluble drugs Apparatus 5 Paddle over disc Rotating stirrer Transdermal drug products Apparatus 6 Cylinder Rotating stirrer Transdermal drug products Apparatus 7 Reciprocating disc Reciprocation Extended-release drug products Rotating bottle Non-USF-NF Extended-release drug products (beads) Diffusion cell (Franz) Non-USF-NF Ointments, Creams, Transdermal drug products

20. Apparatus 1:Rotating Basket – The rotating basket apparatus consists of a basket held by a motor Shaft. The basket holds the sample and rotates in a round flask containing the dissolution medium. The entire flask is immersed in a constant temperature bath set at 37 C. Agitation is provided by rotating the basket. The rotating speed and the position of the basket must meet specific requirements set forth in the current USP. The most common rotating speed for the basket method is 100-150rpm. A disadvantage of the rotating basket is that the formulation may clog to the 40-mesh screen.

21. Apparatus 2:Paddle Method- It   consists of a special coated paddle formed from a blade and a shaft that minimizes turbulence due to stirring. The coated material is inert. The paddle is attached vertically to a variable – speed motor that rotates at a controlled speed.   As per   IP, diameter of the paddle is 74.5+0.5 mm. The tablet or capsule is placed into a round-bottom dissolution flask and the apparatus is housed in a constant temperature water bath maintained at 37°C. Most common operating speeds are 50rpm for solid oral dosage forms and 25 rpm for suspensions. A sinker ,such as few turns of platinum wire may be used to prevent a capsule or tablet from floating . Used for film coated tablets that stick to the vessel walls or to help to position tablet/capsule under the paddle.

22. In-Vitro-In-Vivo Correlation In IVIVC, “C” denotes “Correlation”, which means “the degree of relationship between two variables”. This term does not limit a relationship to only the linear type, but allows for non-linear relationships as well. It is defined as “the predictive mathematical model that describes the relationship between in vitro property (such as rate & extent of dissolution) of a dosage form and in vivo response (such as plasma drug concentration or amount of drug absorbed)”. The main objective of developing and evaluating IVIVC is to use dissolution test to serve as alternate for in vivo study in human beings. USP definition “The establishment of rational relationship b/w a biological property or a parameter derived from a biological property produced by a dosage form and physicochemical property of same dosage form” Conceptually, IVIVC describes a relationship between the in vitro dissolution release versus the in vivo absorption. FDA definition “A predictive mathematical model describing relationship between in-vitro property of a dosage form and in-vivo response.”

23. Correlations of IVIVC Correlations based on the plasma level data Correlations based on the urinary excretion data Correlations based on the pharmacologic response Levels of IVIVC: Level A: The highest category of correlation. It represents point to point correlation between in vitro dissolution and in vivo rate of absorption. Advantages: Serves as alternate for in vivo study, change in manufacturing, procedure or formula can be justified without the need of additional human studies. Providing process control and quality assurance . Determining stable release characteristics of the product over time.

24. Level B: The mean in vitro dissolution time is compare with mean in vivo residence time. It is not point to point correlation. Data can be used for quality control standards. A predictive model for relationship between summary parameters that characterize the in-vitro and in-vivo time course. No point to point correlation • It compares 1. MDT vitro to MDT vivo, 2. MDT vitro to MRT, 3. In-vitro Dissolution Rate Constant. This is of limited interest and least useful for regulatory purposes because more than one kind of plasma curve produces similar MRT. Level C: Mathematical model of relationship between the amount of drug dissolved in-vitro at a particular time and a summary pharmacokinetic parameter that characterizes in- vivo time course. (e.g., Cmax , Tmax , T1/2 or AUC).

25. Application of IVIVC a) Early stages of drug delivery technology development b) Formulation assessment c) Dissolution specifications d) FUTURE BIOWAIVERS : for minor formulation and process changes e) IVIVC parenteral drug delivery : causes of failure of parenteral IVIVC.

26. Reference Brahmankar D.M, Biopharmaceutics and pharmacokinetics, New Delhi, Vallabh Publication,2002 Leon Shargel ,Applied biopharmaceutics &pharmacokinetic; 4 th edition ,page no-429-435. Notari E. Robert, “Biopharmaceutics and clinical pharmacokinetics”, 4 th edition, CRC Press publishers. Dissolution Technologies : http;//www.dissolutiontech.com

27. THANK YOU