Dr. Deny Susanti - Biomedic Generation · PDF filethickener, colorants, flavours, ... • The three techniques commonly employed in drug-excipient compatibility screening are: –Thin

Design and Dosage Form

Dr. Deny Susanti

Example 1

• Aspirin tablet is stable but not as a liquid dosage form

• How to design liquid form?• Soluble or dispersible aspirin tablets-to be dissolved in water

• Note: the resulting solution or suspension is to be

taken immediately

Example 2

• Benzylpenicillin is inactivated by gastric acid

• Susceptible to hydrolysis if stored as a solution

• How to administer to human?

• Formulated for parenteral, rather than for oral and packed as powder

• Use of sodium or potassium salt which readily dissolve upon reconstitution

Example 3

• Diclofenac sodium is inactivated in gastric acid

• It is to be taken orally

• How to administer to human?

• Formulated for enteric coated tablet

• Enteric coat protects the tablet from destruction within the gastric chamber

• Enteric coated dissolves in the small intestine

Phase of Drug Development

Preliminary pre-formulation

Pre-formulation

Early-stage development

Late stage development

Product Characterization-Physical and Chemical evaluations, early stage of pharmacology

Formulation, Delivery, Packaging Development -Determination of dosage forms & Product formulation

Pharmacokinetic and drug disposition, Preclinical Toxicity Testing-Pharmaceutical and in-vitro evaluation

Clinical Trial-In-vivo and clinical evaluationPhase 1 –Human Pharmacology-to evaluate the pharmacokinetic data and tolerance to healthy volunteersPhase 2-Therapeutic Exploratory-to evaluate a drug’s preliminary efficacy and side effect in 100 to 250 patientPhase 3-Therapeutic Confirmatory-large scale clinical trial for safety and efficasy in large patient population

Pre-formulation

• The definition of preformulation proposed by Akers (1976):Preformulation testing encompasses all studies enacted on a new drug compound in order to produce useful information for subsequent formulation of a stable and biopharmaceutically suitable drug dosage form.

• Wells’ book on the subject (1988)Do not neglect these foundations. Good preformulation will inevitably lead to simple and elegant formulations and successful commercial products.

Pre-formulation

• Involves 3 main activities:

– Understanding physico-chemical parameter of a drug• Characterization of drug molecule

– Application of biopharmaceutical principles

– An optimum drug delivery system• Dosage forms

Physico-chemical parameters of a drug

• Characteristic-spectroscopy

• Solubility

• Melting point

• Cristallinity

• Particle size and particle size distribution

• Stability studies (in solid state and solution form)

• Excipient compatibility

Characteristic-Spectroscopy

• To confirm the drug structure and functional groups

• Usually by UV spectroscopy

• Info obtain also provide avenue to quantity the amount of drug in a particular solution (use wavelength at max)

• Other than UV spectroscopy:– Infrared spectroscopy

– Nuclear magnetic resonance spectroscopy

(1H NMR and 13C NMR)

– Mass spectrometry

Solubility

• Establishing solubility characteristics is valuable in developing a formulation and as a first step

• The solubility in various solvent is usually determined in a variety of commonly used solvent and water is the first choice

• For lipophilic drug molecule, some oil may be suitable

• Affects the bioavailability of the drug, the rate of drug release into the dissolution medium and consequently, the therapeutic efficacy of the pharmaceutical product.

Crystallinity

• Need to determine crystal morphology and particle size

• A polymorph is a solid material with two ore more different molecular arrangements and having a distinct crystal species. These difference disappear in the liquid or vapour state

• In general, the stable polymorph exhibits the highest melting point, the lowest solubility, and the maximum chemical stability

Structures of the polymorphs of estrone.

• It is necessary that the preformulation protocol investigates and characterizes these phenomena so that:– the desired forms can be consistently manufactured

– the effects of pharmaceutical manipulations are understood, e.g., granulation, milling and compression

– the effect of storage conditions on the dosage form can be evaluated and predicted, e.g., crystal growth in suspensions, creams and metered dose inhalers (MDIs)

• True polymorphs can be classified into two different types– enantiotropic—one polymorph can be reversibly changed into another

one by varying the temperature or pressure.

– monotropic—the change between the two forms is irreversible

Crystallinity

• Polymorphs generally have different melting points, x-ray diffraction patterns, and solubility, even though they are chemically identical

• Different dissolution rate > affect bioavailability

• Different tensile strength > compression ability

• Different stability at various temperature & pressure

Particle size, shape and surface area

• Various chemical and physical properties of drug substances are affected by their particle size distribution and shape

• Particle size is critical in the dose uniformity and dissolution rate of solid dosage form

Particle size, shape and surface area

• Poorly soluble drugs with low dissolution rate will be more readily bioavailable when administered in a finely subdivided states rather than as a coarse material

• Suspension and creams are more uniform if the ingredients used are in micronized form

Particle size and particle distribution

• Bulk flow, formulation homogeneity and surface area controlled processes such as dissolution and chemical reactivity are directly affected by size, shape & surface morphology of the drug particles as well as particle size distribution

• Size also be a factor in stability of tablets; fine materials are relatively more open to attack from atmospheric oxygen, the humidity, and interacting excipients than are coarse materials.

Chemical stability of active

• Max self-life allowable is 5 years

• Study of intrinsic stability of the active components allow better approaches to formulation, selection of a suitable materials and design of the packaging

• Include both solution and solid state experiments under conditions typical for the handling, formulation, storage, and administration of a drug candidate as well as stability in presence of other excipients

Chemical stability of active

• Critical factor affecting chemical stability in rational dosage form design include:– Temperature & humidity

– pH, ionic strength

– Co-solvent, dosage form diluent

– Light

– Oxygen

• Stress condition utilized are:– Elevated temperature studies

– Stability under high humidity conditions

– Photolytic stability

– Oxidative stability

Excipients

• Knowledge of drug-excipient interactions is therefore very useful to the formulator to enable selecting of suitable and appropriate excipients

• Excipients for a typical tablet contains binder, disintegrants, lubricants and fillers

• Excipients for a typical liquids contains preservatives, thickener, colorants, flavours, sweeteners, buffer and water

• The three techniques commonly employed in drug-excipientcompatibility screening are:– Thin layer chromatography

– Differential thermal analysis

– Diffuse reflectance spectroscopy

Drug-Excipient compatibility

Drug

50% mixture

Excipient

Alternative excipient

DSC

Screening under nitrogen

No interaction

Interaction

Recommend excipient

Yes

TLC

Significant breakdown ?

No

Pre-formulation

• Involves 3 main activity:

– Understanding physico-chemical parameters of drug• Characterization of drug molecule

– Application of biopharmaceutical principle

– An optimum drug delivery• Dosage form

• Pharmacology

– Study of the interaction of biologically active agents with living system (body)

• Pharmacodynamic-

– What the active agent does to the living body

• Pharmacokinetic (ADME)-

– What the body does to the active agent

Biopharmaceutics

• The study of the pharmaceutical factors which affect the fate of the drug after administration

• These factors need to be evaluated in the development of a new drug in order to determine the appropriate dose and dosage interval

Biopharmaceutics

• Influenced by the key interaction between the drug and the body after administration (ADME):– Absorption (the way the drug enters the body and reaches the

bloodstream)

– Distribution (where the drug goes in the body after it has been absorbed)

– Metabolism (how it is change by the body- e.g. in the liver)

– Elimination (the route by which it, or its metabolites, leave the body –e.g. in the urine via the kidney)

Biopharmaceutics

Different steps in the absorption process including the dissolution of the compound from the solid dosage form, interactions with the dissolved material in the gastro-intestinal lumen and the uptake of the compound through the epithelial membrane

• The biopharmaceutical information gathered in the candidate drug selection process regarding the characteristics of the drug molecule (e.g., dissolution, solubility, stability in fluids at the site of administration, enzymatic stability, membrane transport and bioavailability).

This information is important for– to determine suitable formulation types and technologies,

– to set biopharmaceutical targets for formulation development

– to define initial biopharmaceutical test methods and studies needed to reach the targets

– as background data for interpretation of different studies used in the development of a formulation.

Biopharmaceutics

Factor which influence drug absorption

• Physico-chemical properties of drug– Lipophilicity of the drug

• Dosage form of drugs – Rate of drug release from tablet or capsule formulations

– Some dosage forms purposely designed to slow down the dissolution rate of drug at a controlled rate rather than all at once. This is called sustained or controlled release

Factors which influence drug absorption

• Interaction with gastric juice– For pH sensitive drugs

• Patient’s age– Newborn and geriatric are highly susceptible

• Patient’s disease state

• Site of absorption of drugs

• Dose and dosage intervals– Based on bioavailability study

• Drug-drug interaction– As for food-drug interaction, this may retard or enhance drug

absorption

Fate of Drug

• Upon administration of drug into the body, absorption need to happen before we can consider the fate of drug. Before absorption, the following must first take place:

– Release of drug from its dosage form into the biological fluids

– The release drug now in the biological fluids, will be dispersed and move to the absorption site (stomach, lung, skin, rectum, etc.)

Fate of Drug

• Next, the dissolved/released drug will move across the biological membranes (gastric linings, lung membranes, epidermis of skin, etc.) into the systemic circulation. This is called absorption

• Once absorbed, it will be distributed within the blood circulation

• During distribution, drug may bind reversibly to plasma or tissue proteins which act as storage depots in which the bound drug is in equilibrium with free drug in the tissue or plasma

Absorption

Absorption via Passive Diffusion across GIT membrane

Gastrointestinal fluid

Drug in solution

Gastrointestinal membrane

Blood

Partition Partition

DIFFUSIONDrug in solution carried away by circulating blood

Absorption

Absorption via Active Transport across GIT membrane-for lipid-insoluble drugs, need a carrier (enzymes), one way flow

Gastrointestinal fluid

Gastrointestinal membrane

Blood

Drug (in solution)

Drug + carrier

Carrier Drug

Carrier

Partition Partition

Drug in solution carried away by circulating blood

Fate of drug

• After absorption, drug will be metabolised ( e.g. in the liver), leading to:– Inactivation of drug

– Formation of more polar, hydrophilic compounds which is more easily excreted and eliminated. Elimination rate depend on drug’s half life

– Formation of an active moiety, where the original drug is inactive (Pro drug)

• Drug (as it or its metabolised form) will be excreted (via kidney, GIT, skin)

Half-life

• The biological half-life of a drug is used as a measure of how long the drug remains in the body

• It is the time required for the body to eliminate 50% of the drug which the body contained

• Shorter half-life drug requires more frequent dosage interval

Bioavailability

• The rate at which the amount of the administers dose of a drug is able to reach the systemic circulation

Bioavailability

• Assess by measuring drug concentration in a body fluid (often blood plasma) for a period of time after it has been administered

• Plot a graph showing drug plasma concentration against time after administration

• Indicate Therapeutic Range; between max. safe. Conc. (MSC) and min. effective conc. (MEC) given

Bioavailability

• Drug concentration drops below MEC prior to next dose. This is a bad dosage regimen (dose+interval)

• Higher initial dose improve bioavailability

MSC : maximum safe concentrationMEC: minimum effective concentration

Pre-formulation

• Involves 3 main acitivity:

– Understanding physico-chemical parameters of drug• Characterization of drug molecule

– Application of biopharmaceutical principle

– An optimum drug delivery• Dosage form

Why dosage form?

• Mechanism for the safe and convenient delivery of accurate dosage• Protection of a drug substance from destructive influences of

atmospheric oxygen or humidity• Protection from influence of gastric acid after oral administration• To mask taste of offensive drugs• To provide liquid preparation of substances that are either insoluble

or unstable• To provide clear liquid dosage form• To provide time-controlled release of drug• To provide optimal topical administration• To provide for the insertion of a drug into one of the body’s orifices• Provide for placement of drugs into the blood stream• Provide for lung inhalation of drug

Dosage form

• To provide an optimum drug delivery

Dosage form

• At a certain stage during drug development, the dosage form of the drug (eg. a tablet, a capsule or an injection) has to be determined

• Although the formulator is concerned with the pharmaceutical aspect of drug design, there are many other factors that also determine which dosage form(s) is/are to be used. Amongst them are marketing considerations, equipment suitability, packaging requirements, target consumer groups, etc.

Dosage form

• Therapeutic consideration also play an important role in deciding the dosage form to use (eg. fast or slow onset required)

• Bioavailability not an issue for parenterals

Determination of Dosage Form

• Active not absorbed in GIT -> use as injection

• Active destroy by gastric juices -> as injection or enteric coated tablet

• Bronchodilators for fast action -> as inhaler powders or aerosol

• For long acting -> sustained released tablet

• For superficial problem -> use creams or ointments

• For slow release and long action -> controlled released cap/tab or transdermal patch

Common Dosage Forms

Dosage form Comment

Tablets & capsules Convenient & commonest dosage forms but likely to be not good if the drug cannot be absorbed in the alimentary tract or if the patient (e.g. child) cannot swallow them

Injection & infusion Rapid action but impractical for treating chronic (long term) illness

Pessaries & suppositories Can deliver the drug to local area where require but have limited general use

Solution, suspension & elixir

Useful for children and the elderly but are bulky and less useful if the drug is unpalatable or unstable in the presence of water

Ointments, & creams Use is restricted to topical application

Aerosol & dry powder inhalation

Good for drugs required in the lungs but can be difficult to administer the dose correctly

Transdermal patch Convenient if the dose needs to be released over a long period (eg.hormon replacement therapy) but can cause irritation

Benefits of pre-formulation studies

• Systemic way of drug development process

• Development of an effective, stable and safe drug product

• Allow development of an optimal design (dosage form) for administrators and users

• Avoid future drug or dosage related problems

• Avoid wastage of 4M resources (Man, machine, money, material)