- delivery system in which the drug could be available or administered.

Each dosage unit is designed to contain a specified quantity of medication for ease and accuracy of dosage administered.
Each

product is a formulation unique unto

itself

The role of the drug formulation in the delivery of drug to the site of action should not be ignored. Since a drug must be in solution to be absorbed efficiently from the G-I tract, you may expect the bioavailability of a drug to decrease in the order solution > suspension > capsule > tablet > coated tablet. A. Solution dosage forms: - In most cases absorption from an oral solution is rapid and complete, compared with administration in any other oral dosage form.
-

- Some drugs which are poorly soluble in water may be: 1- dissolved in mixed water/alcohol or glycerol solvents (cosolvency), 2- given in the form of a salt (in case of acidic drugs)

3- An oily emulsion or soft gelatin capsules have been used for some compounds with lower aqueous solubility to produce improved bioavailability.

B. Suspension dosage forms: - A well formulated suspension is second to a solution in terms of superior bioavailability. -

A suspension of a finely divided powder will maximize the potential for rapid dissolution. A good correlation can be seen for particle size and absorption rate. The addition of a surface active agent will improve the absorption of very fine particle size suspensions.

Absorption of drugs from aqueous suspensions

C. Capsule dosage forms:

-

The hard gelatin shell should disrupt rapidly and allow the contents to be mixed with the G-I tract contents. If a drug is hydrophobic a dispersing agent should be added to the capsule formulation. These diluents will work to disperse the powder, minimize aggregation and maximize the surface area of the powder.
Tightly packed capsules may have reduced dissolution and bioavailability.

D. Tablet dosage forms:

Blood

The tablet is the most commonly used oral dosage form. It is also quite complex in nature.

1-Ingredients Drug: may be poorly soluble, hydrophobic Lubricant: usually quite hydrophobic Granulating agent: tends to stick the ingredients together Filler: may interact with the drug, etc., should be water soluble Wetting agent: helps the penetration of water into the tablet Disintegration agent: helps to break the tablet apart

Coated tablets are used to mask an unpleasant taste, to protect the tablet ingredients during storage, or to improve the tablets appearance. This coating can add another barrier between the solid drug and drug in solution. This barrier must break down quickly or it may hinder a drug's bioavailability.
-

- Sustained release tablet Another form of coating is enteric coated tablets which are coated with a material which will dissolve in the intestine but remain intact in the stomach.

 In

order to affect dissolution rate based on ones objective, there should be a change in particle size. particle size larger surface area to be wetted dissolution rate faster rate of absorption But for local effect, increased particle size is required

Table 1. Location of processes Process Tablets disintegrate (a suspension forms) Primary Location Stomach Secondary Location(s) Duodenum for enteric coated forms

Drug dissolves from suspension Drug in lipid suspension may be picked up by lacteals (absorption) Drug in solution crosses mucosa (absorption)

Stomach
Duodenum, jejunum, ileum

Duodenum

Duodenum, jejunum Stomach, Ileum, colon

 2-phase

system in which one should be uniformly dispersed into another.

phase should be in small particle size so it can readily mix with dispersion medium.

Dispersed

 Disintegration

is the physical break-up of an intact dosage form to its component aggregates. Disintegration depends on the disintegrant used.

Starch Microcrystalline cellulose

 It

was generally recognized some years ago that a solid drug product had to disintegrate into small particles and release the drug before absorption could take place. For the purpose of monitoring tablet disintegration, USP established an official disintegration test.

 Separate

specifications are given for

uncoated tablets plain coated tablets enteric coated tablets buccal tablets sublingual tablets

 Solid

drug products exempted from disintegration tests Troches Tablets which are intended to be chewed Drug products intended for SR, or prolonged or repeat action

 Excipients

added to the active ingredient to form a dosage form that is convenient for control purposes. - it should be inert, inactive, neither enhances nor diminishes the therapeutic effect of the drug

1.

2.
3. 4.

may affect drug absorption may increase solubility may increase retention time of drug in the GIT may act as carriers to increase diffusion across intestinal wall

In contrast, most excipients may retard drug dissolution and decrease drug absorption

1. Diluents added to increase the bulk/mass of the dosage form eg. Lactose, Dibasic Ca Phosphate, starch, microcrystalline cellulose 2. Binder makes the diluent adhere to the tablet to form a compact mass. Pressure is applied to make the tablets contact. eg. Acacia, alginic acid, gelatin, povidone, etc.

 3.

Lubricant helps to have an easier transfer from one stage of manufacture to another - assist the smooth tableting process. eg. Mag. Stearate, stearic acid, talc, hydrogenated vegetable oil
excessive

magnesium stearate (a hydrophobic lubricant) in the formulation may retard drug dissolution and cause slower drug absorption.

protection uneven coating can cause uneven release of active ingredient

Example:

a. enteric coatings employed to permit safe passage of tablet through the acid environment of the stomach where certain drugs may be destroyed, to the more suitable juices of the intestines where tablet dissolution safely takes place. ( shellac, cellulose acetate phthalate)

 b.

film-coatings employed to protect the drug substance from the destructive influences of moisture, light and air throughout their period of storage or to conceal a bad or bitter taste from the taste buds of the patient. (hydroxypropylmethylcellulose)

c. sugar-coatings conceal bitter taste (liquid glucose, sucrose)

4. Surfactants Low conc. of surfactant = decrease surface tension = rate of dissolution? High conc. of surfactant = formation of micelles = rate of dissolution?

 Polymorphism

refers to the arrangement of a drug in various crystal forms or Polymorphs Polymorphs have the same chemical structure but different physical properties such as: solubility, density, hardness and compression characteristics

 Some

polymorphic crystals may have much lower aqueous solubility than the amorphous forms, causing a product to be incompletely absorbed. Ex. Chloramphenicol
with the LOWEST free energy is

Crystal

stable

 Solvate

Drug + solvent = crystal

Hydrates Drug + H2O = crystal

 In

general, the crystalline form of drugs are more rigid and thermodynamically more stable than the amorphous form. The crystal form with the lowest free energy is the most stable polymorph. A change in crystal form may cause problems in manufacturing the product. For example, a change in crystal structure of the drug may cause cracking in a tablet or even inability for a granulation to be compressed to form a tablet.

Erythromycin dehydrate dissolves faster than the monohydrate & anhydrous form

less

hydrated faster dissolution

Ampicillin anhydrous would have faster dissolution than trihydrate but it is less absorbed

 Clathrates-

cages the drug to make it more stable (protective) and soluble (reacts with the solvent) e.g. gallic acid, urea, zeolite

 Drugs

in like vehicles stay in the vehicle

(e.g., aqueous in aqueous)

Drugs

in unlike vehicles move to the skin surface

(e.g., aqueous in lipid)

 Hydrophobic

compounds absorbed at rate dependent on o/w coefficient Hydrophilic compounds poorly absorbed through pores at rate inversely proportional to molecular size Membrane lining the airway is relatively impermeable to unionised form of drug

 Rapid

absorption solutions or powders of aqueously soluble salts Slower/prolonged absorption suspensions or powders of less soluble salts, liposome encapsulated drug, microspheres Some drugs absorbed by saturable active transport mechanisms (e.g. Na cromoglycate) and macromolecules by transcytosis

 Rate

of absorption high if size<100Da however molecules with molecular weight uo to app. 1000Da have a relatively good BA without absorption enhancers. Hydrophilic drugs absorbed by non-specific diffusion through aqueous pores (paracellular transport) Lipophilic drugs likely absorbed through transcellular route at a slower rate

 pH-partition

theory relevant but nasal epithelia is very sensitive so pH of formulation must be appropriately controlled Partioning is not the only factor controlling absorption

 Maximising

the systemic availabilty of drugs administered via the nasal route 1. Improve nasal residence time 2. Enhance nasal absorption 3. Modify drug structure to change physicochemical properties

 Drugs

either dissolve in rectal fluid/melt on mucous layer Drug dissolves in rectum then is absorbed into bloodstream by haemorrhoidal veins Due to osmotic effects of dissolving vehicle water is attracted to the rectum painful sensation Drugs diffuse out of vehicle and towards rectal membranes

 Sequence

of events

MELTING SPREADING SEDIMENTATION WETTING DISSOLUTION

United State Pharmacopoeia (USP) definition of IVIVC The establishment of a rational relationship between a biological property, or a parameter derived from a biological property produced by a dosage form, and a physicochemical property or characteristic of the same dosage Form. Food and Drug Administration (FDA) definition of IVIVC 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 invitro property of a dosage form and an in-vivo response. e.g., amount of drug absorbed, thus allowing an evaluation of the QC specifications, change in process, site, formulation and application for a biowaiver etc.

 In-vitro

in-vivo correlation (IVIVC) establishes a relationship between a biological property of the drug (such as pharmacodynamic effect or plasma drug concentration) and a physicochemical property of the drug product containing the drug substance, such as dissolution rate

 The

may require changes in the composition, manufacturing process, equipment, and batch sizes. In order to prove the validity of a new formulation, which is bioequivalent with a target formulation, a considerable amount of efforts is required to study bioequivalence (BE)/bioavailability(BA).

optimization of formulations

The

to utilize in vitro dissolution profiles as a surrogate for in vivo bioequivalence and to support biowaivers
TESTING IN HUMANS

main purpose of an IVIVC model

LESS

 The

Biopharmaceutic Drug Classification system, BCS, is a predictive approach to relate certain physicochemical characteristics of a drug substance and drug product to the dugs in-vivo bioavailability

BCS guidelines are provided by USFDA, WHO, and EMEA Class I: HIGH solubility / High permeability, Class II: LOW solubility / High permeability, Class III: HIGH solubility / LOW permeability Class IV: LOW solubility / LOW permeability
BCS Criteria highly soluble drugs: therapeutic dose is soluble in 250 mL (pH 1 7.5) highly permeable drugs: extent of absorption: > 90% (rapidly dissolving: no less than 85% within 30 min, USP II / 50 rpm /pH 1 - 6.8 ; always considered similar if 85% released in less than 15 min)

 Refer

to articles for more information on IVIVC. Prepare for tomorrow Bioavailability and Bioequivalence
For

test look at the outcomes in Study Units 1, 2 &3. Chapters 13 and 14 in Applied Biopharmaceutics in Pharmacokinetics (Shargell) Chapter 2 in Biopharmaceutics and Pharmacokinetics (Venkateswarlu)