1. the physical and chemical properties of the drug substance;

2. the route of drug administration, including the anatomic and physiologic nature of the application site (eg, oral, topical, injectable, implant, transdermal patch, etc);

3. desired pharmacodynamic effect (eg, immediate or prolonged activity);

4. toxicologic properties of the drug; 5. safety of excipients; and 6. effect of excipients and dosage form on drug delivery.

rational design of drug products

Pharmaceutic Factors Affecting Drug BioavailabilityConsiderations in the design of a drug product that will deliver active drug with the desired bioavailability characteristics include

1. the type of drug product (eg, solution, suspension, suppository),

2. the nature of the excipients in the drug product, 3. the physicochemical properties of the drug molecule,

and 4. the route of drug administration.

Pharmaceutic Factors Affecting Drug Bioavailability

Physicochemical Properties for Consideration in Drug Product DesignpKa and pH profile

Necessary for optimum stability and solubility of the final product.

Particle size May affect the solubility of the drug and therefore the dissolution rate of the product.

Polymorphism The ability of a drug to exist in various crystal forms may change the solubility of the drug. Also, the stability of each form is important, because polymorphs may convert from one form to another.

Hygroscopicity Moisture absorption may affect the physical structure as well as stability of the product.

Partition coefficient

May give some indication of the relative affinity of the drug for oil and water. A drug that has high affinity for oil may have poor release and dissolution from the drug product.

Excipient interaction

The compatibility of the excipients with the drug and sometimes trace elements in excipients may affect the stability of the product. It is important to have specifications of all raw materials.

pH stability profile

The stability of solutions is often affected by the pH of the vehicle; furthermore, because the pH in the stomach and gut is different, knowledge of the stability profile would help to avoid or prevent degradation of the product during storage or after administration.

Physicochemical Properties for Consideration in Drug Product Design

Solubility, pH, and Drug Absorption• The is a plot of the solubility of the drug at various solubility

– pH profile physiologic pH values. • the natural pH environment of the gastrointestinal tract

varies from acidic in the stomach to slightly alkaline in the small intestine.

• A basic drug is more soluble in an acidic medium, forming a soluble salt. Conversely, an acid drug is more soluble in the intestine, forming a soluble salt at the more alkaline pH.

• Solubility may be improved with the addition of an acidic or basic excipient.

• Solubilization of aspirin, for example, may be increased by the addition of an alkaline buffer.

Physicochemical Properties for Consideration in Drug Product Design

Stability, pH, and Drug Absorption.• The stability–pH profile is a plot of the reaction rate

constant for drug degradation versus pH.• If drug decomposition occurs by acid or base catalysis,

some prediction of degradation of the drug in the gastrointestinal tract may be made.

• For example, erythromycin has a pH-dependent stability profile. In acidic medium, as in the stomach, erythromycin decomposition occurs rapidly, whereas in neutral or alkaline pH, the drug is relatively stable.

Particle Size and Drug Absorption• The effective surface area of a drug is increased

enormously by a reduction in the particle size. • the greater the surface area, the more rapid is the rate of

drug dissolution. • Particle size and particle size distribution studies are

important for drugs that have low water solubility. • Griseofulvin, nitrofurantoin, and many steroids are drugs

with low aqueous solubility; reduction of the particle size by milling to a micronized form has improved the oral absorption of these drugs.

Physicochemical Properties for Consideration in Drug Product Design

Physicochemical Properties for Consideration in Drug Product Design

Polymorphism, Solvates, and Drug Absorption Polymorphism refers to the arrangement of a drug substance in various crystal forms or polymorphs.

• Amorphous forms are noncrystalline forms, • solvates are forms that contain a solvent (solvate) or water

(hydrate), and• desolvated solvates are forms that are made by removing the

solvent from the solvate.• Polymorphs have the same chemical structure but different physical

properties, such as solubility, density, hardness, and compression characteristics.

• In general, the crystal form that has the lowest free energy is the most stable polymorph.

Chloramphenicol, for example, has several crystal forms, and when given orally as a suspension, the drug concentration in the body was found to be dependent on the percent of -polymorph in the suspension. The form is more soluble and better absorbed,

Comparison of mean blood serum levels obtained with chloramphenicol palmitate suspensions containing varying ratios of and polymorphs, following single oral dose

equivalent to 1.5 g chloramphenicol. Percentage polymorph in the suspension.

Effect of Excipients on the Pharmacokinetic Parameters of Oral Drug Products

Excipients Example k a T MAX AUCDisintegrants Avicel, Explotab /—

Lubricants Talc, hydrogenated vegetable oil /—

Coating agent Hydroxypropylmethyl cellulose — — —Enteric coat Cellulose acetate phthalate /—

Sustained-release agents Methylcellulose, ethylcellulose/—

Sustained-release agents (waxy agents)

Castorwax, Carbowax/—

Sustained-release agents (gum/viscous)

Veegum, Keltrol /—

This may be concentration and drug dependent.      = Increase,      = decrease, — = no effect, k a = absorption rate constant, t max = time for peak drug concentration in plasma, AUC = area under the plasma drug concentration–time curve.

For example, shows that an excessive quantity of magnesium stearate (a hydrophobic lubricant) in the formulation may retard drug dissolution and slow the rate of drug absorption. The total amount of drug absorbed may also be reduced (). To prevent this problem, the lubricant level should be decreased or a different lubricant selected.

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. In-vitro drug dissolution studies are most often used for monitoring drug product stability and manufacturing process control.

dissolution and drug release testing may be used for: • Batch-to-batch drug release uniformity • Stability • Predicting in-vivo performance• To accessing therapeutic efficacy & bioequivalence. • Requirement for regulatory approval for product

marketing• Scale-up and postapproval changes (SUPAC)

Dissolution and Drug Release Testing

Dissolution Conditionsdissolution vesselsdissolution vessels range in size from several milliliters to several liters. The shape may be round-bottomed or flat, so the tablet might lie in a different position in different experiments. The usual volume of the medium is 500–1000 mL. (up to 2000 mL)

dissolution medium 0.1 N HCl, phosphate buffer, simulated gastric juice, water, and simulated intestinal juice, depending on the nature of the drug product and the location in the gastrointestinal tract where the drug is expected to dissolve.

temperature Most dissolution tests are performed at 37°C. However, for transdermal drug products, the recommended temperature is 32°C.

agitationThe most common rotating speed for the basket method is 100 rpm And for Apparatus 2 are 50 rpm for solid oral dosage forms and 25 rpm for suspensions.

Problems of Variable Control in Dissolution Testing• Depending on the particular dosage form involved, the variables may or may not exert a

pronounced effect on the rate of dissolution of the drug or drug product. Variations of 25% or more may occur with the same type of equipment and procedure.

• The centering and alignment of the paddle is critical in the paddle method. • Turbulence can create increased agitation, resulting in a higher dissolution rate. • Wobbling and tilting due to worn equipment should be avoided. • the basket method is more sensitive to clogging due to gummy materials.• dissolved gas in the medium may form air bubbles on the surface of the dosage form unit

and can affect dissolution in both the basket and paddle methods.• In the absence of in-vivo data, it is generally impossible to make valid conclusions about

bioavailability from the dissolution data alone. The use of various testing methods makes it even more difficult to interpret dissolution results, because there is no simple correlation among dissolution results obtained with various methods

• For many drug products, the dissolution rates are higher with the paddle method. Dissolution results at 50 rpm with the paddle method may be equivalent to dissolution at 100 rpm with the basket method.

• the composition of the formulation as well as the process variables in manufacturing may both be important.

• No simple correlation can be made for dissolution results obtained with different methods.

• the selection of the dissolution method is based on the type of drug product to be tested.

Dissolution ApparatusApparatus Name Drug ProductApparatus 1 Rotating basket TabletsApparatus 2 Paddle Tablets, capsules, modified drug

products, suspensionsApparatus 3 Reciprocating

cylinderExtended-release drug products

Apparatus 4 Flow cell Drug products containing low-water-soluble drugs

Apparatus 5 Paddle over disk Transdermal drug productsApparatus 6 Cylinder Transdermal drug productsApparatus 7 Reciprocating disk Extended-release drug productsRotating bottle (Non-USP-NF) Extended-release drug products

(beads)Diffusion cell (Franz)

(Non-USP-NF) Ointments, creams, transdermal drug products

Conditions that May Affect Drug Dissolution and Release

1. Drug substance• Particle size• Polymorph• Surface area• Chemical stability in dissolution

media

2. Formulation of drug product• Excipients (lubricants,

suspending agents, etc)

3. Medium• pH• Molarity• Volume• Co-solvents, added

enzymes/surfactants

4. Hydrodynamics• Agitation rate• Shape of dissolution vessel• Placement of tablet in vessel• Sinkers (for floating products

and products that stick to side of vessel)

5. Temperature of medium 6. Apparatus

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

1. disintegration of the drug product and subsequent release of the drug,

2. dissolution of the drug in an aqueous environment, and

3. absorption across cell membranes into the systemic circulation.

Rate-Limiting Steps in Drug Absorption

In-Vitro–In-Vivo Correlation

An In-vitro in-vivo correlation (IVIVC) has been defined by the Food and Drug Administration (FDA) as "a predictive mathematical model describing the relationship between an in-vitro property of a dosage form and an in-vivo response".The United States Pharmacopoeia (USP) also defines IVIVC as "the establishment of a relationship between a biological property, or a parameter derived from a biological property produced from a dosage form, and a physicochemical property of the same dosage form".Typically, the parameter derived from the biological property is AUC or Cmax, while the physicochemical property is the in vitro dissolution profile.

The main role's of IVIVC are:1. The first and main role of establishing IVIVC is to use dissolution test as a

surrogate for human studies.2. Supports and / or validates the use of dissolution methods and specifications.3. Assists in quality control during manufacturing and selecting appropriate

formulations

Level In vitro In vivoA Dissolution curve Input (absorption) Curves

B Statistical moments: meandissolution time (MDT)

Statistical moments: meanresidence time (MRT), mean absorption time (MAT), etc

C Disintegration time, Time to have 10, 50, 90% dissolved, Dissolution rate, Dissolution efficiency

Cmax, Tmax, Ka, Time to have 10,50,90% absorbed, AUC (total or cumulative),

Various parameters used in IVIVC depending on the level.

Class Solubility Permeability Absorption rate control

IVIVC expectation

BCS Class I High High Gastric emptying IVIVC expected if dissolution rate is slow than gastric emptying rate otherwise limited or no correlation

BCS Class II LOW High Dissolution IVIVC expected if in vitro dissolution rate is similar to in vivo dissolution, unless very high dose

BCS Class III High Low Permeability Absorption (permeability) is rate determining, limited or no IVIVC with dissolution

BCS Class IV Low Low Not defined (case by case)

Limited or no IVIVC is expected

Biopharmaceutics drug clarification system.

In Vivo Method1. Pharmacokinetic Methods:

Indirect measurement of therapeutic effectiveness of the drug a. Blood level studies (plasma or serum) b. Urinary excretion studiesc. Assay of other biological material (saliva, CSF, bile, fecal recovery

study, etc)2. Pharmacodynamic Methods:

Direct measurement of therapeutic effectiveness of the drug a. Acute pharmacological response b. Therapeutic response

IN-VITRO METHOD a. Release characteristics Drug dissolution testing modulesb. Permeation studies Diffusion model, Everted sac, everted ring

technique, caco-2 cells

IN-SITU METHOD Doluisio method, single perfusion method

In-Vitro–In-Vivo Correlation

Failure to correlate in-vitro dissolution to in-vivo absorption

Nature of exceptions: 1. Drug failed in dissolution test and yet well absorbed ; 2. No or poor correlation between dissolution (in- vitro bioavailability) and in-

vivo absorptionProbable causes: 3. Complexity of drug absorption process

• a product that involves fatty components may retain longer in GI tract; • effect of digestive enzymes play an important role in in-vivo dissolution

which may not be adequately simulated in a dissolution media4. Weakness of in-vitro dissolution design

e.g. among two sustained-release quinidine gluconate tablets one is completely bioavailable and the other is partially absorbed.

Two models are used: Model 1: Using acid media as well as acid followed by pH 7.4 interestingly don’t distinguish two products well.Model 2: Using water or pH 5.4 buffer as buffer media clearly distinguishes two products. The condition of Model 1 is consistent with physiologic condition of stomach, but the procedure would be misleading as a quality control tool in this case.

Biopharmaceutic considerations in Drug Product Designing

1. Prime Consideration• Safety [finished drug product shouldn’t produce any

additional side effect/discomfort due to drug/excipients, excipients should be inactive]

• Efficacy [ Drug product should should deliver drug of maximum bioavailability and minimum adverse effect]

2. Pharmacodynamic consideration• Therapeutic objective

- e.g. drug to treat acute illness should release the drug rapidly like nitroglycerine for angina pectoris; - for prophylactic treatment of chronic disease like asthma extended release type is preferred

• Toxic effect• Adverse reactions

Biopharmaceutic considerations in Drug Product Designing

3. Drug consideration - Physicochemical properties of drug

•pH, •aqueous solubility, •polymorphism, •particle size, •dissolution etc.

If a drug has low aqueous solubility and an IV injection is desired then a soluble salt of the drug is preferred

Biopharmaceutic considerations in Drug Product Designing

4. Drug product consideration1. Pharmacokinetics of drug e.g. therapeutic window;

i) drug conc. Higher than t.w. may initiate more intense pharmacodynamic & toxic effect whereas below that conc. Could be sub-therapeutic;

ii) Drugs with narrow T.W. Size of dose & dosing frequency to be adjusted precisely to get desired effect with a safe dose

2. Bioavailability of the druga) Stability of drug in GI tract and intestine, e.g. penicillin G is

unstable in acid media of stomach, so addition of buffer or use of enteric coating in the formulation will protect from degradation at low pH;

b) Some drugs have poor bioavailability due to intense first-pass effect , in this case a higher oral dose (propranolol) or alternative route (Insulin) will be required

Biopharmaceutic considerations in Drug Product Designing

Dose consideration• Size of dose

based on inherent property of drug molecule plus its apparent VD which determines target Cp for desired therapeutic effect; for some drugs several doses are required to allow individualized dosing

• Dosing frequency If a drug has a short duration of action due to short elimination t1/2 then the drug must be given more frequently