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 evaluation Phase 1 Human Pharmacology-to evaluate the pharmacokinetic data and tolerance to healthy volunteers Phase 2-Therapeutic Exploratory-to evaluate a drug s preliminary efficacy and side effect in 100 to 250 patient Phase 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 ( 1 H NMR and 13 C 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-excipient compatibility screening are: Thin layer chromatography Differential thermal analysis Diffuse reflectance spectroscopy
Drug-Excipient compatibility Drug No interaction 50% mixture DSC Recommend excipient Excipient Screening under nitrogen Interaction TLC Alternative excipient Yes 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
Biopharmaceutics 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.
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 Gastrointestinal membrane Blood Drug in solution DIFFUSION Drug in solution carried away by circulating blood Partition Partition
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 + carrier Drug (in solution) Carrier Drug Carrier Drug in solution carried away by circulating blood Partition Partition
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 concentration MEC: 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 Tablets & capsules Injection & infusion Pessaries & suppositories Solution, suspension & elixir Ointments, & creams Aerosol & dry powder inhalation Transdermal patch Comment 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 Rapid action but impractical for treating chronic (long term) illness Can deliver the drug to local area where require but have limited general use Useful for children and the elderly but are bulky and less useful if the drug is unpalatable or unstable in the presence of water Use is restricted to topical application Good for drugs required in the lungs but can be difficult to administer the dose correctly 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)