Dosage Form Design Murat Kizaibek

The Need for Dosage Forms

To provide the mechanism for the safe and convenient delivery of accurate dosage To protect the drug substance from the atmosphere To protect the drug substance from the gastric acid (EC tablet) To conceal the bitter, salty, or offensive taste or odor To provide liquid preparations of insoluble drugs

The Need for Dosage Forms (continued) To provide clear liquid dosage forms (solutions) To provide rate-controlled drug action To provide topical drug action (ointments, creams, patches, ophthalmic, otic, nasal) To provide for insertion into body cavity To provide for placement into bloodstream To provide for inhalation therapy

General Considerations in Dosage Form Design

the nature of the illness --normally (systemic use or oral) : tablet or capsule --an emergency in which the patient may be comatose or unable to take oral medication: injection --motion sickness, nausea,and vomiting: tablets and skin patches are used for prevention and suppositories and injections for treatment.

age --infants and children younger than 5 years of age: flavored liquid preparations --young patient who has a productive cough or is vomiting, gagging, or simply rebellious: injection, suppository anticipated condition of the patient --patients who have difficulty in swallowing tablets whole: chewable tablets

Design of Drug Products Effectiveness Safety Reliability Stability –Physical –Chemical –Microbiological

Design of Drug Products (continued) Pharmaceutical elegance –Appearance –Organoleptic properties Convenience –Ease of use –Dosing frequency –Consumer acceptance

Preformulation Studies Chemical characterization Physical characterization

Physical Description Solids, liquids, gases Chemical Properties –Structure, form, reactivity Physical Properties –particle size, crystalline structure, melting point, solubility Biological Properties –Ability to get to site of action and elicit a response Herbal medicines: – powder of herbs or extracts, viscosity

Microscopic Examination Particle size Particle size range Crystal structure Particle shape

Heat of Vaporization the amount of heat required to convert 1g of a liquid into the vapor without a change in temperature and is measured in calories. Vapor pressure （ aerosol ） Volatile drugs can migrate within a solid dosage form Personnel exposure

Melting Point Purity determination Identity

The Phase Rule Phase diagrams Phase diagrams are valuable for interpreting interactions between two or more components, relating not only to melting point depression and possible liquefaction at room temperature but also the formation of solid solutions, coprecipitates, and other solid-state interactions.

Particle Size Dissolution rate Bioavailability Content uniformity Taste Texture Color Stability Flow characteristics Sedimentation rates The following characteristics of a drug substance are affected by the particle size distribution:

Polymorphism Crystalline form Amorphous form at least one third of all organic compounds exhibit polymorphism. Melting point variation Solubility differences

Solubility Some aqueous solubility required for therapeutic efficacy Equilibrium solubility Solubility in different solvents Chemical modification of the drug into salt or ester forms is frequently used to increase solubility.

Solubility and Particle Size Small increases in solubility can be achieved by particle size reduction. Decreases in particle size may enhance dissolution rates.

Solubility and pH pH can affect solubility.

Dissolution Dissolution may be rate-limiting step in the absorption of poorly soluble drugs. Can affect onset, intensity, and duration of response and control overall bioavailability of the drug from the dosage form

Membrane Permeability pKa, solubility, and dissolution rate data can provide an indication of absorption.

pKa/Dissociation Constants Extent of dissociation or ionization Dependent on pH of medium Can affect absorption, distribution, and elimination

Partition Coefficient Octanol:water partition coefficient often used in formulation development

Drug and Drug Product Stability Physical stability Chemical stability Shelf life of 2-3 years is generally desired

Drug Stability: Mechanisms of Degradation Hydrolysis, solvolysis Oxidation Other processes

Drug and Drug Product Stability: Kinetics and Shelf Life Chemical stability:active ingredient retains its chemical integrity and labeled potency within the specified limits. Physical stability:appearance, palatability, uniformity, dissolution, and suspendability Microbiological stability:microbial growth Therapeutic stability:The therapeutic effect remains unchanged. Toxicologic stability:No signifi cant increase in toxicity occurs.

Rate Reactions Change of drug concentration with respect to time

ZERO-ORDER RATE REACTIONS FIRST-ORDER RATE REACTIONS C t lnC t C t

Q 10 Method of Shelf Life Estimation Shelf life estimation Reasonable estimates can often be made using the Q value of 3.

Enhancing Stability of Drug Products Excipients may be added to protect the drug –Antioxidants –Preservatives –Chelating agents –Buffering agents

Stability Testing Done at each stage of product development Product containers and closures must be considered Temperature and humidity studies Light studies Changes in physical appearance, color, odor, taste, texture Chemical changes of drug degradation Pharmacist is last professional to check for quality and stability prior to dispensing

Herbal drugs: preformulation

1. processing 2. powder of extract or powder of plant material? 3. volatile? 4. taste or odor 5. solvent of extraction? 6. dense and hard materials 7.bioguided fractionation